Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[O:12][CH:11]=[N:10][C:9]=1[C:13](OC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([C:8]1[O:12][CH:11]=[N:10][C:9]=1[CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ncoc1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ncoc1Cc1ccccc1

Procedure:
Methyl 5-benzyl-4-oxazolecarboxylate is reduced with lithium aluminium hydride in tetrahydrofuran to give 5-benzyl-4-hydroxymethyloxazole, which by reacting with thionyl chloride is converted to 5-benzyl-4-chloromethyloxazole.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:27]([F:29])([F:28])[F:30])[CH:20]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1-c1c(Br)cnn1C
Yield: 83.3 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.027 g, 0.12 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 6 (0.051 g, 0.10 mmol, 81%) as a white solid. LCMS m/z (%)=503 (M+H79Br35Cl, 78), 505 (M+H81Br35Cl, 100), 507 (M+H81Br37Cl, 28). 1H NMR (400 MHz, acetone-d6) δ: 8.52 (s, 1H), 8.27 (s, 1H), 8.13 (s, 1H), 7.74 (b, J=8.7 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.14 (d, J=9.0 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C@H:34]([OH:37])[CH2:35][OH:36])=[CH:28][CH:27]=1)[C:3]([NH:5][C@@H:6]([C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[Cl:17])=[O:8])=[O:4].C(N(CC)CC)C.Cl[Si:46]([CH3:49])([CH3:48])[CH3:47]>C(OCC)(=O)C>[NH2:1][C@H:2]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C@H:34]([O:37][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH2:35][O:36][Si:46]([CH3:49])([CH3:48])[CH3:47])=[CH:28][CH:27]=1)[C:3]([NH:5][C@@H:6]([C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[Cl:17])=[O:8])=[O:4]
Reactant: C[Si](C)(C)Cl
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OC[C@H](O)CO)cc1)C(=O)Nc1ccc(I)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OC[C@@H](CO[Si](C)(C)C)O[Si](C)(C)C)cc1)C(=O)Nc1ccc(I)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,3S)-2-{(R)-2-amino-2-[4-((R)-2,3-dihydroxy-propoxy)-phenyl]-acetylamino}-N-(2-chloro-4-iodo-phenyl)-3-phenyl-butyramide (330 mg, 0.44 mmol) in dry, degassed tetrahydrofuran (5 mL) were added triethylamine (277 μL, 1.98 mmol) and chlorotrimethylsilane (230 μL, 1.76 mmol) and the mixture stirred at ambient temperature for 30 minutes. The resulting suspension was diluted with ethyl acetate (50 mL) and washed with brine (2×50 mL). The combined brine layers were back extracted with ethyl acetate (2×50 mL), the combined organic layers dried over sodium sulfate, filtered and concentrated in vacuo to give crude (2S,3S)-2-{(R)-2-amino-2-[4-((S)-2,3-bis-trimethylsilanyloxy-propoxy)-phenyl]-acetylamino}-N-(2-chloro-4-iodo-phenyl)-3-phenyl-butyramide which was of adequate purity for subsequent use in step 6 without additional purification (330 mg, 96%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Cl[CH2:45][C:46]1[N:47]=[N:48][CH:49]=[CH:50][CH:51]=1.BrCC1OC(C(F)(F)F)=CC=1>>[N:48]1[CH:49]=[CH:50][CH:51]=[C:46]([CH2:45][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])[N:47]=1
Reactant: ClCc1cccnn1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2cccnn2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, and 3-(chloromethyl)pyridazine to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-(pyridazin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (13%) as a colorless solid: mp 81-82° C.; 1H NMR (300 MHz, CDCl3) δ9.18-9.14 (m, 1H), 7.58-7.44 (m, 2H), 7.28-7.15 (m, 2H), 7.12-7.02 (m, 2H), 6.47 (s, 1H), 6.43 (s, 1H), 5.39-5.22 (m, 2H), 4.84 (ABq, 2H), 4.60-4.49 (m, 2H), 3.10-2.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.1, 161.9, 161.4, 158.4, 151.1, 141.6, 132.4, 129.0, 127.3, 126.0, 123.9, 123.8, 120.0, 119.9, 118.8, 109.6, 93.3, 80.6, 72.4, 57.8, 44.6, 29.0; MS (ES+) m/z 372.3 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[NH2:13][C@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][C@H:15]1[O:25][CH3:26]>C([O-])(O)=O.[Na+]>[CH2:5]([O:4][C:2]([NH:13][C@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][C@H:15]1[O:25][CH3:26])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)N1CC[C@H](N)[C@H](OC)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](OC)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Benzyl chloroformate (3.3 ml) was added dropwise to a cold solution of Cis(±)ethyl 4-amino-3-methoxypiperidine-1-carboxylate hydrochloride salt (Intermediate 21; 5 g) in saturated NaHCO3. The mixture was stirred at room temperature for 14 h. The white precipitate was filtered, washed well with water, dried in vacuo to give the title compound as a white solid (6.66 g). MS (ES) MH+: 336 for C17H24N2O5; NMR: 1.21 (t, 3H), 1.52-1.67 (m, 2H), 3.08 (m, 2H), 3.28 (s, 3H), 3.41 (s, 2H), 3.74-3.92 (m, 2H), 3.96 (m, 2H), 4.14 (m, 1H), 5.10 (s, 2H), 7.24 (d, 1H), 7.44 (m, 5H).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.C(N(C(C)C)CC)(C)C>CCO>[Br:8][C:6]1[N:7]=[C:2]([NH:19][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[NH:10][CH:11]=[CH:12]3)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Nc1ncc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1ncc(Br)nc1Nc1ccc2[nH]ccc2c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 42 %

Procedure:
To a stirred suspension of 3,5-dibromopyrazin-2-amine (3.48 g, 13.7 mmol) and 1H-indol-5-amine (2.00 g, 15.0 mmol) in EtOH (3.5 mL) was added diisopropylethylamine [DIEA](2.60 mL, 15.0 mmol). The resulting mixture was stirred for 48 hr at 80° C., after which it was partitioned between EtOAc and H2O. The organic layer was separated, after which it was washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo to yield a residue that was purified via silica gel chromatography eluting with 1:1 EtOAc:hexanes to yield the title compound (1.75 g, 42%) as a red/brown solid. 1H NMR (DMSO-d6, 300 MHz): δ 10.98 (s, 1H), 8.22 (s, 1H), 7.83 (s, 1H), 7.31-7.28 (m, 3H), 7.19 (d, J=8.7 Hz, 1H), 6.43 (s, 2H), 6.36 (s, 1H); HPLC retention time: 2.07 minutes; MS ESI (m/z): 304.2/306.2 (M+1)+, calc. 303.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[S:22]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23]1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]1[C:6]([C:7](=[O:9])[CH:27]([C:24]2[CH:25]=[CH:26][S:22][CH:23]=2)[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1C(=O)O
Reactant: CCOC(=O)Cc1ccsc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)c1ccnn1C)c1ccsc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 22.7 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (300 mg, 2.4 mmol) in DMF (7 mL) was added CDI (372 mg, 2.6 mmol), and the reaction mixture was heated to 50° C. for two hours. Then the mixture was cooled to −5° C., a solution of ethyl 2-(thiophen-3-yl)acetate (444 mg, 2.6 mmol) in DMF (1 mL) was added to the mixture and NaH (330 mg, 8.2 mmol) was added in portions. The mixture was stirred at 0° C. for 10 minutes, then warmed to room temperature and stirred for 1 hour. Ice water was added, followed by a standard aqueous/EtOAc workup. Crude was purified by column chromatography (PE:EtOAc=5:1) (150 mg, yield: 22.7%).
Reaction SMILES: ClCCCl.[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[O:14]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O.C(O)(=O)C>[O:14]([C:21]1[CH:22]=[C:23]([NH:24][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([Br:5])[CH:7]=2)[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: O=Cc1cccc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: Brc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
EX-595A) To a 1,2-dichloroethane (90 mL) solution of 3-bromobenzaldehyde (5.60 g, 30.3 mmol) was added 3-phenoxyaniline (5.60 g, 30.2 mmol), NaB(OAc)3H (8.26 g, 39.0 mmol) and acetic acid (1.8 mL, 31. mmol). The cloudy solution was stirred at room temperature for 1.5 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4) and evaporated to yield 10.49 g (98%) of the desired N-(3-phenoxyphenyl)[(3-bromophenyl)methyl]amine product as a light brown oil. 1H NMR (CDCl3) δ 4.26 (s, 2H), 6.27 (s, 1H), 6.38 (d, 2H), 7.00 (d, 2H), 7.13 (m, 2H), 7.19 (t, 1H), 7.26 (d, 1H), 7.30 (m, 2H), 7.38 (d, 1H), 7.96 (s, 1H). The formation of the desired product was monitored by the disappearance of the aldehyde peak (δ˜10) and the formation of the benzyl peak (δ 4.26) in the 1H NMR spectrum.
Reaction SMILES: [C:1]([C:9]1[C:17]([N+:18]([O-])=O)=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:18][C:17]1[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14]
Reactant: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CCCCOc1cc(C(=O)O)cc(N)c1C(=O)c1ccccc1

Procedure:
To a stirred mixture of 4-benzoyl-3-n-butoxy-5-nitrobenzoic acid (5.1 g), pyridine (25 ml), and water (25 ml), sodium dithionite (10.2 g) is added in portions. The mixture is heated on a steam bath for 1 hour and is then evaporated in vacuo. The remaining material is dissolved in water (about 50 ml) and the solution is acidified with conc. hydrochloric acid (about 15 ml). After cooling, the resulting precipitate is collected by filtration and washed with water. After drying and recrystallization twice from ethanol, 5-amino-4-benzoyl-3-n-butoxybenzoic acid is obtained with a melting point of 202.5° -203.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH:8]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[CH3:9])[C:6](=[S:19])[NH:5][C:4](=[O:20])[CH:3]=1.[N:21]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[NH2:21][C:3]1[C:4](=[O:20])[NH:5][C:6](=[S:19])[N:7]([CH:8]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[CH3:9])[C:2]=1[NH2:1]
Reactant: O=N[O-]
Reactant: CC(c1nc2ccccc2[nH]1)n1c(N)cc(=O)[nH]c1=S
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(c1nc2ccccc2[nH]1)n1c(N)c(N)c(=O)[nH]c1=S
Reaction time: 0.33 h

Procedure:
To 6-amino-1-[1-(1H-benzimidazol-2-yl)ethyl]-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.21 g, 0.74 mmol, obtained from Example 9(d)) in acetic acid (2 mL) was added, dropwise, a solution of sodium nitrite (0.056 g, 0.81 mmol) in H2O (0.5 mL). After 50 minutes sodium dithionite (0.26 g, 1.5 mmol) was added and the reaction was stirred 20 minutes, followed by evaporation of acetic acid in vacuo and addition of water (25 mL). The precipitated solid was collected by filtration, washed with H2O and dried giving the title compound, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[C:5]([Cl:23])=[C:4]([Cl:24])[N:3]=1.[C:25](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N:9]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:22])([F:20])[F:21])[CH3:25])[C:5]([Cl:23])=[C:4]([Cl:24])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(Nc2c(Cl)c(Cl)nc(Cl)c2Cl)c(C(F)(F)F)c1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CN(c1ccc([N+](=O)[O-])cc1C(F)(F)F)c1c(Cl)c(Cl)nc(Cl)c1Cl
Reaction time: 2 h

Procedure:
N-(2,3,5,6-Tetrachloro-4-pyridyl)-N-(4-nitro-2-trifluoromethylphenyl)amine (2.0 grams; 0.005 mole), 30 ml. of acetone, 6.0 grams of sodium carbonate and 6 ml. of dimethyl sulfate were mixed and refluxed. After 2 hours, TLC showed no evidence of product. After 8 hours, TLC showed evidence of some product formation. After about sixteen hours, the reaction mixture was quenched by adding water, heating for one hour, and then allowing to cool. Product precipitated and was separated by filtration. It was purified by passing it through a silica gel column with toluene as eluent. Yield was 0.31 gram, m.p. 152°-155° C. Elemental analysis showed
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1.[N+:16]([C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[N+:16]([C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Reactant: CNCCc1ccc(NS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCOc1ccc([N+](=O)[O-])cc1)CCc1ccc(NS(C)(=O)=O)cc1

Procedure:
A solution of N-methyl-4-methanesulphonamidophenethylamine (1.0 g) (see Preparation 8), 2-(4-nitrophenoxy)ethyl bromide (1.2 g) (C.A., 54, 11046a), potassium carbonate (0.67 g) and sodium iodide (0.72 g) in acetonitrile (100 ml) was stirred at reflux for 3 days. On evaporation to dryness, the residual oil was partitioned between water and methylene chloride. After two further extractions with methylene chloride, the organic portions were combined, washed with saturated brine solution, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness. The resultant yellow oil was taken up in hot methanol, cooled and the title compound crystallised as a colourless solid, (1.2 g).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C@H:16]([CH2:17][C@H:18]([O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:19][CH2:20]1)[CH2:15][CH2:14]3)[OH:6]>C1COCC1>[Si:27]([O:26][C@@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:8]2([CH3:9])[C@H:10]3[CH2:11][CH2:12][C@@H:7]2[CH:5]([OH:6])[C:4]#[CH:3])[CH2:17]1)([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(O)C#C[Si](C)(C)C)CC[C@@H]32)C1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C#CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (n-Bu)4N+F− 1M in THF (0.72 mL, 0.72 mmol) was added to a solution of 3-trimethylsilyl-1-[3α-(t-butyidiphenylsilyloxy)-5α-androstan-17β-yl]-2-propyn-1-ol (310 mg, 0.48 mmol) in THF (10 mL) and the resulting mixture was stirred at RT for 30 min. The reaction mixture was worked up as in Example 7 to afford after purification by flash column chromatography using petroleum ether/acetone 82/18 as elution solvent the compound named above.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.C1CCC(N=C=NC2CCCCC2)CC1.[C:26]([O:30][C:31]([N:33]1[CH2:36][CH:35]([C:37](O)=[O:38])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1CCCCC1>CN(C1C=CN=CC=1)C.ClCCl>[C:26]([O:30][C:31]([N:33]1[CH2:36][CH:35]([C:37]([CH:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])=[O:38])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C(=O)C2C(=O)OC(C)(C)OC2=O)C1
Reaction time: 8 h

Procedure:
Meldrum's acid (0.85 g, 5.97 mmol), DCC (1.22 g, 5.97 mmol), and DMAP (1.45 g, 11.94 mmol) were successively added to a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.2 g, 5.97 mmol) in dichloromethane (25 mL) at room temperature. The reaction mixture was stirred overnight and then diluted by addition of cyclohexane (25 mL). The precipitate of dicyclohexyl urea was then filtered and rinsed with diethyl ether (100 mL). The mother liquors were diluted with DCM (100 mL) and washed with a 1M solution of aqueous HCl (2×30 mL), dried over sodium sulfate, filtered and concentrated to dryness. After trituration in diethyl ether the title compound was obtained as a white solid (1.9 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([F:13])[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]([F:22])[CH:8]=1)[CH3:2].[N+](=[CH2:26])=[N-].O>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([CH:5]1[CH2:26][CH:6]1[C:7]1[CH:12]=[C:11]([F:13])[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]([F:22])[CH:8]=1)=[O:23])[CH3:2]
Reactant: CCOC(=O)/C=C/c1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CC1c1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
After (E)-3-(4-benzyloxy-3,5-difluoro-phenyl)-acrylic acid ethyl ester (2.5 g, 7.85 mmol) obtained in Step C of Preparation Example 2 was dissolved in THF (10 mL), diazomethane solution (94 mL, 23.55 mmol, 0.25M ether) was added thereto. After the reactant was cooled to 0˜5° C., palladium(II) acetate (0.29 g, 1.30 mmol) was added slowly thereto, and the mixture was stirred at room temperature for 5 hours. After the termination of the reaction, the reactant was added with water and then extracted. The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography (eluent EtOAc/Hex=1/10) to obtain the title compound (2.27 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][N:31]([CH:33](OC)OC)[CH3:32]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([C:14]2[CH:15]=[CH:16][C:17]([C:20](=[O:28])[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:30][N:31]([CH3:33])[CH3:32])=[CH:18][CH:19]=2)[CH2:9][C:10]([OH:13])([CH3:12])[CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(OC)N(C)C
Reactant: CC1(O)CC(NC(=O)OC(C)(C)C)(c2ccc(C(=O)Cc3ccccc3)cc2)C1
Solvent: Cc1ccccc1
Product: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CC(C)(O)C2)cc1)c1ccccc1

Procedure:
To a solution of compound 2-3 (3.96 g, 10 mmol) in toluene (20 mL) was added DMFDMA (9.2 g, 35 mmol) and the mixture was heated at reflux for 4 hours. The mixture was cooled and the formed white solid was collected. After washed by PE, the solid was dried in vacuum to get the product 2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[C:11]([C:15]([O:17]C)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.O.O>[C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[C:11]([C:15]([OH:17])=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nc(NC(=O)OC(C)(C)C)cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(NC(=O)OC(C)(C)C)nc1C(=O)O
Reaction time: 8 h
Yield: 81.5 %

Procedure:
Methyl 4-(tert-butoxycarbonylamino)-1-methyl-1H-imidazole-2-carboxylate (5.0 g, 19.59 mmol) in 120 ml of 1:1 THF/H2O was added 8 g of NaOH in 30 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1:1). The aqueous solution was adjusted to pH 4.0 with 20% H3PO4 and extracted with EtAc (4×60 ml). The organic solutions were combined, dried over MgSO4, filtered, evaporated and crystallized with ethanol/EtAc/Hexane to afford 3.85 g (81%) of the title product. 1H NMR (DMSO) 9.32 (s, 1H), 7.29 (s, 1H), 3.57 (s, 3H), 1.42 (s, 9H); 13C NMR 172.45, 159.78, 136.93, 135.44, 132.85, 79.50, 35.57, 28.07; MS m/z− 240.8 (M−H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]([F:22])([F:21])[F:20])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]([CH3:17])[C:13](OC)=[O:14])[C:7]([CH3:18])=[CH:6]2)#[N:2].[Li+].[BH4-]>C1COCC1>[OH:14][CH2:13][CH:12]([N:8]1[C:9]2[C:5](=[C:4]([C:19]([F:22])([F:20])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH:6]=[C:7]1[CH3:18])[CH3:17]
Reactant: COC(=O)C(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To an ice-cold solution of methyl 2-(5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl)propanoate (Example 1) (0.263 g, 0.848 mmol) in THF (5 mL) was added dropwise LiBH4 (2M in THF) (1.695 mL, 3.39 mmol). After complete addition of the reducing agent, the cold bath was removed and the mixture was stirred at rt. After 2 h, the reaction mixture was cooled in an ice bath and a saturated aqueous NH4Cl solution (15 mL) was added slowly. The mixture was then diluted with EtOAc (40 mL) and treated slowly with 1N HCl (10 mL). The phases were separated and the aqueous phase was washed with EtOAc (20 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel using a 20-60% EtOAc-hexane gradient to give 1-(1-hydroxypropan-2-yl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.212 g, 83% yield) as a white solid: MS (ESI): m/z 283 (MH+).