Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].F[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1.C(OCC)(=O)C>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:28]2[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=2)=[CH:15][CH:16]=1)[C:18]([OH:20])=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Oc2ccc(C=O)cc2)cc1)C(=O)O
Reaction time: 0.25 h

Procedure:
Dissolve N-tert-butoxycarbonyl-L-tyrosine (2.42 Kg, 8.3 moles) in dry DMF (7.26 L) under argon and still till complete dissolution. Add K2CO3 (3.57 Kg, 25.81 moles), 4-fluorobenzaldeyde (5.34 Kg, 43.01 moles) and stir at 70±5° C. for 48 h under argon. Cool the reaction mixture less than 30° C. Poured the reaction mixture in water (75 L) and stir for 15 min. Add ethyl acetate (40 L) and stir for 30 min. Separate the organic layer and aqueous layer was acidified with HCl (6M) to pH 2. Solid precipitated was dissolved in ethyl acetate (40 L) and aqueous layer was separated. Organic layer was washed with brine (40 L), dried on sodium sulfate and evaporate solvent under reduced pressure. Observed HPLC purity (93.4%) and chiral purity by HPLC (100%). Dry with anhydrous MgSO4 and evaporate under reduced pressure. Pale yellow solid (3.06 Kg, 99.3%). 1H NMR (300 MHz, DMSO-d6): 9.89 (s, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.00 (overlapped d, J=9.0 Hz, 4H), 4.63 (m, 1H), 3.2 (m, 1H), 3.06 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].CN([CH:13]=[O:14])C>O>[OH:14][C:13]1[NH:1][C:2]2[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: Cc1cccc(N)c1N
Reactant: CN(C)C=O
Solvent: O
Product: Cc1cccc2nc(O)[nH]c12
Temperature: 92.5 °C

Procedure:
2,3-Diaminotoluene (5 g, 41 mmol), 1,1-carbonyldiimidazole (7.3 g, 45 mmol) and 50 mL of anhydrous DMF are successively introduced into a 250 mL two-necked flask under an argon atmosphere, with magnetic stirring. After heating the mixture at 90-95° C. for 4 h, the solvent is distilled off under vacuum and the residue obtained is taken up in water (250 mL) and extracted with ethyl acetate (3×250 mL). The insoluble product formed during the extraction is recovered (4.8 g) and the combined organic phases are washed again with saturated NaCl solution, dried over MgSO4, filtered and concentrated to give a further 1.2 g of desired product (6 g, quantitative). 1H NMR (300 MHz, δ ppm) DMSO D6: 2.27 (s, 3H), 6.72 (m, 2H), 6.82 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>CC([O-])=O.CC([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd+2].C1(C)C=CC=CC=1>[CH3:27][Si:28]([C:31]#[C:32][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1)([CH3:30])[CH3:29]
Reactant: CCOC(=O)c1ncn2c1CN=C(c1ccccc1)c1cc(Br)ccc1-2
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncn2c1CN=C(c1ccccc1)c1cc(C#C[Si](C)(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.9 %

Procedure:
A mixture of bromide 5 (0.3 g, 0.73 mmol), trimethylsilylacetylene (0.143 g, 1.46 mmol) and bis(triphenylphosphine)-palladium-(II) acetate (55 mg, 0.073 mmol) in a mixed solvent system of toluene (20 mL) and anhydrous TEA (50 mL) was heated to reflux under argon. After stirring for 12 hours at reflux, the mixture was cooled to room temperature and the precipitate which formed was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was treated with a saturated aqueous solution of NaHCO3 (20 mL), and extracted with CHCl3 (3×25 mL). The combined extracts were washed with brine and dried (Na2SO4). After removal of solvent under reduced pressure, the residue was purified by flash chromatography (silica gel, EtOAc) to afford 6 (XLiXHeII-048) as a white solid (0.29 g, 93%). This benzodiazepine can also be obtained from 2 in 45% yield by following the same procedure 6 (XLiXHeII-048): mp: 170-172° C.; IR (KBr) 2958, 2152, 1718 cm−1; 1H NMR (CDCl3) δ 0.23 (s, 9H), 1.42 (t, 3H, J=7.2 Hz), 4.04 (d, 1H, J=12.6 Hz), 4.41 (m, 2H, J=7.2 Hz), 6.23 (d, 1H, J=12.6 Hz), 7.35-7.55 (m, 7H), 7.73 (dd, 1H, J=8.3 Hz, J=1.9 Hz), 7.93 (s, 1H); MS (EI) m/e (relative intensity) 427 (M+, 76), 412 (5), 381 (55), 353 (100) 303 (10), 287 (7). Anal. Calcd. for C25H25N3O2Si.1/3 EtOAc: C, 69.22; H, 6.01; N, 9.20. Found: C, 68.87; H, 5.81; N, 9.37.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][CH:48]=[CH:47][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=2)=[CH:13][CH:12]=1.Br[C:52]1[N:53]([CH2:57][CH2:58][CH2:59][O:60][CH3:61])[CH:54]=[CH:55][N:56]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:50]=[CH:49][CH:48]=[CH:47][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:52]3[N:53]([CH2:57][CH2:58][CH2:59][O:60][CH3:61])[CH:54]=[CH:55][N:56]=3)[CH:33]=2)=[CH:15][CH:16]=1
Reactant: COCCCn1ccnc1Br
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COCCCn1ccnc1-c1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1

Procedure:
The mixture of 0.050 g of tetrakis(triphenylphosphine)palladium(0) in 1.0 ml of 1,2-dimethoxyethane is admixed with the solution of 0.319 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyloxy]piperidine-1-carboxylate and 0.144 g of 2-bromo-1-(3-methoxypropyl)-1H-imidazole in 2.0 ml of 1,2-dimethoxyethane and 0.3 ml of ethanol. The reaction mixture is admixed with 0.9 ml of 2M sodium carbonate solution and stirred at reflux over 20 hours. The resulting reaction solution is concentrated by evaporation, admixed with 1:1 water/brine mixture (30 ml) and extracted with ethyl acetate (2×30 ml). The organic phases are washed with brine (30 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.15 (97:3 dichloromethane-methanol); Rt=523.
Reaction SMILES: CCC1C2CC([CH:11]([OH:22])[C:12]3C4C(=CC=CC=4)N=CC=3)N(CC2)C1.N1C=CC=CC=1.[CH3:29][NH:30][C:31]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43]([C:45]3[N:46]=[CH:47][N:48]([C:50]([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH:49]=3)=[O:44])[CH:39]=2)[CH:34]=1)=[O:32].Cl.[O:70]1CC[CH2:72][CH2:71]1>C(OCC)(=O)C>[OH:44][C@@:43]([C:38]1[CH:37]=[CH:36][C:35]2[C:40](=[CH:41][CH:42]=[C:33]([C:31]([NH:30][CH3:29])=[O:32])[CH:34]=2)[CH:39]=1)([C:45]1[N:46]=[CH:47][N:48]([C:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:49]=1)[CH2:72][C:71]([O:22][CH2:11][CH3:12])=[O:70]
Reactant: C1CCOC1
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: CCC1CN2CCC1CC2C(O)c1ccnc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@](O)(c1ccc2cc(C(=O)NC)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.33 h
Yield: 80 %

Procedure:
Under argon atmosphere, 0.37 g (1.25 mmol, 1.25 equivalent) of hydrocinchonine was added to 4.7 mL (2.5 mmol, 2.5 equivalent) of the solution of ethyl bromozincacetate in tetrahydrofuran obtained in Example 43 at 4˜5° C. 0.32 mL (4 mmol, 4 equivalents) of pyridine was added dropwise at 5˜6° C. The mixture was stirred at 3˜6° C. for 20 minutes. A solution of 0.52 g (1 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 5.2 mL of THF was added dropwise at −36˜−34° C. The mixture was stirred at −40˜−34° C. for 1 hour and 15 minutes. Further, 1.9 mL (1 mmol, 1 equivalent) of the solution of ethyl bromozincacetate in tetrahydrofuran obtained in Example 43 was added dropwise at −40˜−35° C. The mixture was stirred at −40˜−38° C. for 2 hours. 15 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 30 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After concentration under reduced pressure, 5 mL of IPE was added to the concentration residue, this was recrystallized, crystals were filtered, and washed with 3 mL of IPE. After washing, vacuum drying (40° C.) to a constant weight afforded 0.49 g of ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 80%, enantiomer excess 90.9% ee).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:8]([C:25]([NH2:27])=[O:26])=[CH:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20](O)([CH3:22])[CH3:21])[C:11]=2[N:24]=1.[OH-].[Na+].C(=O)(O)[O-:31].[Na+].[Cl:35][CH2:36][C:37]#[N:38]>O>[NH2:6][C:7]1[C:8]([C:25]([NH2:27])=[O:26])=[CH:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]([NH:38][C:37](=[O:31])[CH2:36][Cl:35])([CH3:21])[CH3:22])[C:11]=2[N:24]=1
Reactant: N#CCCl
Reactant: O=C([O-])O
Reactant: CC(C)(O)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21)NC(=O)CCl
Reaction time: 1 h
Yield: 80 %

Procedure:
Concentrated sulfuric acid (1.0 mL) was added dropwise to a solution of 43 (120 mg, 0.102 mmol) in chloroacetonitrile (1.0 mL) at 0° C. Stirring continued at this temperature for 1 h, then the reaction was diluted with water (5 mL) and the pH adjusted to 8-9 with 1N sodium hydroxide then aqueous saturated sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (50 mL×3) then the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (5-10% methanol in methylene chloride gradient) to afford the title compound (56, 120 mg, 80%). NH4OAc standard conditions. DAD Retention time =6.59 min. M+H=374. 1H NMR (300 MHz, CDCl3): Δ 8.39 (br s, 1H), 8.27 (s, 1H), 7.80 (d, J=7.3 Hz, 1H), 7.36-7.34 (m, 2H), 7.22 (dd, J=7.3, 7.3 Hz, 1H), 6.83 (br s, 2H), 5.80 (br s, 2H), 4.28 (s, 2H), 3.87 (s, 2H), 1.55 (s, 6H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:22][C:21](=[O:23])[C:20]4[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=4[O:24][CH3:25])[N:14]=3)=[CH:9][CH:8]=2)[CH2:3]1.[CH:28]1([CH:31]=O)[CH2:30][CH2:29]1.[H][H]>C(O)C.O=[Pt]=O>[CH:28]1([CH2:31][NH:1][CH:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:12]=[CH:11][C:10]([C:13]4[NH:22][C:21](=[O:23])[C:20]5[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=5[O:24][CH3:25])[N:14]=4)=[CH:9][CH:8]=3)[CH2:3]2)[CH2:30][CH2:29]1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N)C4)cc3)nc2c1
Reactant: [H][H]
Reactant: O=CC1CC1
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(NCC5CC5)C4)cc3)nc2c1

Procedure:
A suspension of 2-(4-(3-aminopyrrolidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (14) (0.21 mmol) in ethanol (30 mL) was treated with PtO2 (0.050 g) followed by cyclopropanecarbaldehyde (0.100 mL). The reaction was stirred under 1 atmosphere of hydrogen for 24 hours, filtered through Celite, with ethanol washes, concentrated, and purified by flash chromatography on silica gel, eluting to afford the title compound 15.
Reaction SMILES: [F:1][C:2]([F:31])([CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18]([CH2:19][C@@H:20]([OH:30])[CH2:21][CH2:22]2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10])[CH2:3][C:4]([OH:7])([CH3:6])[CH3:5].[CH2:32]([O:34]C(=O)C(CC(F)(F)C[C@H]([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)C(C[C@@H](OC4CCCCO4)CC2)=CC3)CC1)C)C(OCC)=O)[CH3:33].CC1C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)C)(=O)C>CO.N1C=CC=CC=1>[C:32]([O:30][C@H:20]1[CH2:21][CH2:22][C@@:23]2([CH3:24])[C:18](=[CH:17][CH2:16][C@@H:15]3[C@@H:25]2[CH2:26][CH2:27][C@@:28]2([CH3:29])[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[C@H:9]([CH3:10])[CH2:8][C:2]([F:31])([F:1])[CH2:3][C:4]([OH:7])([CH3:6])[CH3:5])[CH2:19]1)(=[O:34])[CH3:33]
Reactant: C[C@H](CC(F)(F)CC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCOC(=O)C(CC(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CC(F)(F)CC(C)(C)O)[C@@]4(C)CC[C@@H]32)C1
Yield: 96 %

Procedure:
The THP-ether (13) (26 mg, 0.0498 mmol) in methanol (4 ml) and THP (9) (4 ml) was treated with a catalytic amount of TsOH at room temperature for 1 hr. The usual work-up (ethyl acetate for extraction) gave the crude diol (21.4 mg). This diol was treated with acetic anhydride (1 ml) and pyridine (1 ml) at room temperature for 14 hr. The usual work-up (ethyl acetate for extraction) gave a crude product, which was applied to a column of silica gel (5 g). Elution with benzene-ethyl acetate (10:1) provided the acetate (14) (23.0 mg, 96%); mp 168°-170° C. (methanol). 1H-NMR δ: 0.82 (3H, s, 18-H3), 1.02 (3H, s, 19-H3), 1.07 (3H, d, J=6 Hz, 21-H3), 1.35 (6H, s, 26-H3 and 27-H 3), 2.03 (3H, s, acetyl), 4.55 (1H, m, 3-H), 5.36 (1H, m, 6-H). High resolution MS Calcd for C27H42F2O (M+ --CH3COOH): 420, 3202. Found: 420, 3206.
Reaction SMILES: C([O:9][CH2:10][C@:11]12[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:46])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:45]=[CH:44][C:36]([C:37]([O:39]C(C)(C)C)=[O:38])=[CH:35][CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)(=O)C1C=CC=CC=1.[OH-].[Li+]>O1CCOCC1.O>[OH:9][CH2:10][C@:11]12[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:46])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:45]=[CH:44][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1
Reactant: C=C(C)[C@@H]1CC[C@]2(COC(=O)c3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Reaction time: 24 h
Yield: 39.6 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(benzoyloxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (7.2 g, 10.21 mmol) in 1,4-dioxane (75 ml) and water (25 ml) was added lithium hydroxide (1.285 g, 30.6 mmol) and the mixture was stirred at 75° C. Dioxane (50 ml) was added to dissolve all solids and the stirring was continued for 24 h. The solvent was removed and the residue was redissolved into CH2Cl2, the insoluble white solid was collected to afford 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (2.2 g, 39.5%) LCMS: m/e 545.4 (MH+), 2.68 min (method 2).
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=1)([CH3:4])[CH3:3].[CH:16]([Mg]Br)([CH3:18])[CH3:17].Cl>O1CCOCC1.O1CCCC1.[Cu]I>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]([CH:11]([C:12]#[N:13])[C:14]#[N:15])[CH:16]([CH3:18])[CH3:17])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)[Mg]Br
Reactant: CC(C)(O)c1cc(C=C(C#N)C#N)no1
Agent: [Cu]I
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)C(c1cc(C(C)(C)O)on1)C(C#N)C#N
Reaction time: 1 h

Procedure:
1.02 g of {[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]methylidene}malononitrile was dissolved in 50 ml of 1,4-dioxane. Thereto, 0.05 g of copper(I) iodide was added and 15 ml of a 1 M solution of i-propylmagnesium bromide in tetrahydrofuran was then added under ice-cooling. The mixture was stirred for 1 hour under ice-cooling. The reaction mixture was added to 0.1 M hydrochloric acid and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.40 g of {1-[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]-2-methylpropyl}malononitrile.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][CH2:4][NH:5][C:6](=[O:26])[C:7]1[CH:12]=[C:11]([NH2:13])[C:10]([NH:14][CH3:15])=[CH:9][C:8]=1[N:16]1[CH2:21][CH2:20][CH:19]([C:22]([F:25])([F:24])[F:23])[CH2:18][CH2:17]1.[C:29]([O:33][C:34](=[O:48])[NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([N:44]=[C:45]=S)[C:38]=1[Cl:47])([CH3:32])([CH3:31])[CH3:30].CC(C)N=C=NC(C)C>CN(C=O)C>[F:28][C:2]([F:1])([F:27])[CH2:3][CH2:4][NH:5][C:6]([C:7]1[C:8]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([F:23])([F:24])[F:25])[CH2:18][CH2:17]2)=[CH:9][C:10]2[N:14]([CH3:15])[C:45]([NH:44][C:39]3[C:40]([Cl:43])=[CH:41][CH:42]=[C:37]([CH2:36][NH:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:48])[C:38]=3[Cl:47])=[N:13][C:11]=2[CH:12]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C(=O)NCCC(F)(F)F)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)OC(C)(C)C)c2Cl)nc2cc(C(=O)NCCC(F)(F)F)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound is prepared in analogy to 1e from N-(3,3,3-trifluoro-propyl)-2-[4-trifluoromethyl-piperidinyl]-4-methylamino-5-amino-benzoic acid amide (2.3 g, 5.6 mmol), (2,4-dichloro-3-isothiocyanato-benzyl)-carbamic acid tert.-butyl ester (compound B; 1.85 g, 5.6 mmol), DIC (1.0 mL) and DMF (10 mL).
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH2:14]([OH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:14]([O:20][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [Na]
Product: CCCCCCOc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of sodium (230 mg, 10 mmol) in 1-hexanol (15 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol). The mixture was stirred at 50° C. for 2 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the wanted compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][CH2:9][CH:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Br[CH2:26][F:27].O>CN(C=O)C>[NH2:2][C@@H:3]([CH2:8][CH2:9][CH:10]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:26][F:27])=[CH:20][CH:21]=1)[C:11]([O:13][CH3:14])=[O:12])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(CC[C@H](N)C(=O)OC)Cc1ccc(O)cc1
Reactant: FCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CC[C@H](N)C(=O)OC)Cc1ccc(OCF)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
Dimethyl (2S)-2-amino-5-(4-hydroxybenzyl)hexanedioate hydrochloride (200 mg, 0.54 mmol) were solved in DMF (5 ml) and at 0° C. sodium hydride (34 mg, 1.14 mmol) were added. After 30 min, bromofluoromethane (1.35 mmol) were added and the resulting mixture was stirred at 0° C. for one hour. The mixture was then poured into water and extracted three times with methylene chloride. The organic phase was dried with sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography to yield 37 mg (20.8%) of the product.
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]([O:12][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(Cl)c(O)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cnc(Cl)c(OC2CCCCO2)c1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 6-chloro-5-hydroxynicotinate (703 mg) in toluene (15 mL) were added 3,4-dihydro-2H-pyran (685 μL) and pyridinium p-toluenesulfonate (94 mg), and the mixture was stirred at room temperature for 2 hr and further at 60° C. for 1.5 hr. The reaction mixture was poured into water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (546 mg) as a white solid.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)(O)[O-].[Na+].[C:15]([N:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:20]([O:35][CH3:36])[CH2:19]1)(=[O:17])[NH2:16]>C1COCC1>[CH2:27]([O:26][C:25]([NH:24][C@H:21]1[CH2:22][CH2:23][N:18]([C:15]2[O:17][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:16]=2)[CH2:19][C@H:20]1[O:35][CH3:36])=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)n1
Temperature: 70 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
Ethyl bromopyruvate (2.93 g, 15 mmol) and sodium bicarbonate (2.10 g, 25 mmol) were added to a solution of cis(±)-benzyl (1-carbamoyl-3-methoxypiperidin-4-yl)carbamate obtained in Example (103b) (1.4 g, 4.56 mmol) in THF (30 mL), and the mixture was stirred at 70° C. for three hours. The insoluble matter was filtered off, followed by dilution with ethyl acetate. This was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1, 2/1, 4/1) to obtain 1.46 g of the title compound as a colorless solid (79%).