Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[S:10][CH:9]=1)=[O:7])C.Cl>O>[O:16]1[CH2:15][CH2:14][CH:13]([C:11]2[S:10][CH:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)c1csc(C2CCOCC2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1csc(C2CCOCC2)c1
Reaction time: 1 h
Yield: 85.9 %

Procedure:
Potassium hydroxide (0.56 g, 10 mmol) in water (2 mL) was added to 5-(tetrahydro-pyran-4-yl)-thiophene-3-carboxylic acid ethyl ester (3.36 mmol) in IMS (6 mL). The reaction mixture was stirred for 1 hour then water was added and the mixture acidified to pH 7 with 1 N hydrochloric acid and then extracted with diethyl ether. The organic solution was dried over magnesium sulphate, filtered and the solvent evaporated to give the title compound (613 mg). LCMS m/z 211 [M−H]− RT=2.53 min (Analytical Method 4).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][C:6]=1[Cl:7].C([Li])CCC.CON(C)[C:23](=[O:25])[CH3:24]>C(OCC)C>[Cl:7][C:6]1[S:5][C:4]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:3][C:2]=1[C:23](=[O:25])[CH3:24]
Reactant: Clc1sc(CN2CCOCC2)cc1Br
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(=O)c1cc(CN2CCOCC2)sc1Cl
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 36.1 %

Procedure:
4-((4-Bromo-5-chloro-2-thienyl)methyl)morpholine (Preparation 62, 7.65 g) is dissolved in diethyl ether (75 mL) and is cooled to −75° C. A solution of n-butyllithium (2.5 M in hexane, 11.0 mL) is added via addition funnel, maintaining the temperature below −68° C. The reaction is stirred for 15 minutes at −70° C. and allowed to warm to 0° C. A solution of N-methoxy-N-methylacetamide (3.09 g) in ether (5 mL) is added via addition funnel, maintaining the temperature below 5° C. The reaction is stirred at 0° C. for 1 h and allowed to warm to rt. The reaction is quenched with saturated aq. NH4Cl solution (50 mL) and made basic with sat. aq. NaHCO3. The mixture is extracted with ethyl acetate (3×125 mL). The combined organic layers are washed with sat. NaHCO3 (2×100 mL) and brine (50 mL). The combined aqueous washes are back-extracted with ethyl acetate (100 mL). The organic layers are combined, dried (Na2SO4), and concentrated in vacuo to a yellow oil. The crude product is chromatographed, eluting with 25% ethyl acetate/heptane to afford 2.42 g (37%) of the title compound. Physical characteristics: 1H NMR (400 MHz, DMSO-d6) δ7.33, 3.64, 3.58, 2.51; IR (liq.) 2854, 2809, 1673, 1456, 1372, 1351, 1328, 1243, 1212, 1165, 1118, 1034, 1008, 867, 618 cm−1; HRMS (FAB) m/z 260.0506 (C11H14ClNO2S+H). Anal. Found: C, 50.77; H, 5.51; N, 5.35; Cl, 13.24; S, 12.00.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:23][O:24][CH:25]([O:33][CH3:34])[CH2:26][NH:27][C@@H:28]([CH2:30][CH2:31][CH3:32])[CH3:29]>>[CH3:23][O:24][CH:25]([O:33][CH3:34])[CH2:26][N:27]([C@@H:28]([CH2:30][CH2:31][CH3:32])[CH3:29])[C:17](=[O:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12][C:11]1[CH:20]=[CH:21][CH:22]=[C:9]([C:7]2[CH:6]=[N:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=2)[CH:10]=1
Reactant: CC(C)n1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Reactant: CCC[C@@H](C)NCC(OC)OC
Product: CCC[C@@H](C)N(CC(OC)OC)C(=O)CCOCCc1cccc(-c2cnn(C(C)C)c2)c1

Procedure:
The subtitled compound (100 mg) was prepared from 3-(3-(1-isopropyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 20 Step iii)] and ((R)—N-(2,2-dimethoxyethyl)pentan-2-amine [Preparation 10] using a similar method to that described in Example 18, Step iii). MS [M+H-MeOH]+=428 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 8.01 and 8.00 (2×s, 1H), 7.79 (s, 1H), 7.42-7.34 (m, 2H), 7.23 (t, J=7.7 Hz, 1H), 7.05 (d, J=7.7 Hz, 1H), 4.56 and 4.40 (2×t, J=5.3 Hz, 1H), 4.53 (septet, J=6.7 Hz, 1H), 4.26-4.16 and 3.96-3.86 (2×m, 1H), 3.75-3.64 (m, 4H), 3.34 (s, 3H), 3.32 (s, 3H), 3.25-3.10 (m, 2H), 2.84 (t, J=6.5 Hz, 2H), 2.72-2.50 (m, 2H), 1.60-1.14 (m, 4H), 1.51 (d, J=6.9 Hz, 6H), 1.10 and 1.09 (2×d, J=6.7 Hz, 3H), 0.86 (t, J=7.3 Hz, 3H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[N+:16]([O-])=O)[CH:2]([CH3:4])[CH3:3]>C1(C)C=CC=CC=1.[Pt]>[NH2:16][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:6]=1[NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC(C)CNc1c(N)cnc2ccccc12
Yield: 100.6 %

Procedure:
4-Isobutylamino-3-nitroquinoline (31.5 g, 0.1284 moles) from Step (A) above, was dissolved in 300 ml of toluene, and about one g of platinum on charcoal was added thereto. The resulting mixture was hydrogenated on a Parr apparatus for one and one-half hours. The mixture was then heated and filtered. Toluene was removed from the filtrate by rotary evaporation to provide 27.8 g of crude 3-amino-4-(isobutylamino)quinoline. Recrystallization twice from ethyl acetate/hexane provided 18.8 g of purified product, m.p. 98°-100° C. Analysis: Calculated for C13H17N3 : % C, 72.5; % H, 8.0; % N, 19.5; Found: % C, 73.2; % H, 7.8; % N, 19.7.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[C:8]([CH2:26][CH2:27][CH2:28][CH3:29])=[N:9][N:10]([C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:24])[CH2:22][CH3:23])[CH:17]=[CH:16][C:15]=3[Cl:25])[C:11]=2[C:12]#[N:13])=[C:4]([F:32])[CH:3]=1.C1(C)C=CC=CC=1.[C:40]([NH:44][S:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1B(O)O)(=[O:47])=[O:46])([CH3:43])([CH3:42])[CH3:41].[OH-].[Na+]>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.CCCCCC.CCOC(C)=O>[CH2:26]([C:8]1[C:7]([CH2:6][C:5]2[CH:30]=[CH:31][C:2]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=3[S:45](=[O:47])(=[O:46])[NH:44][C:40]([CH3:41])([CH3:43])[CH3:42])=[CH:3][C:4]=2[F:32])=[C:11]([C:12]#[N:13])[N:10]([C:14]2[CH:19]=[C:18]([NH:20][C:21](=[O:24])[CH2:22][CH3:23])[CH:17]=[CH:16][C:15]=2[Cl:25])[N:9]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Reactant: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(C#N)c1Cc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(C#N)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Temperature: 90 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
A reaction flask was charged with 155 mg (0.299 mmol) of 4-(4-bromo-2-fluorobenzyl)-3-n-butyl-1-[2-chloro-5-(propionylamino)phenyl]-1H-pyrazole-5-carbonitrile (from Step H), 3.5 mL of toluene, 2.4 mL of ethanol, 615 μL (0.598 mmol) of a 250 mg/mL solution of 2-(N-t-butylsulfamoyl)phenylboronic acid (from Step I) in ethanol, 950 μL (1.20 mmol) of 1.25N NaOH, and 17 mg of tetrakis(triphenylphosphine)palladium(0). The mixture was stirred under N2 at 90° C. for 5 hours, then cooled and concentrated. The residue was partitioned between 30 mL of ethyl acetate and 25 mL of H2O. The organic layer was washed with brine, dried (Na2SO4), filtered, and evaporated in vacuo. The yellow residual oil was flash chromatographed on silica gel (elution with 3:1 and then 1:1 hexane-EtOAc) to give a 77% yield of the title compound as a slightly yellow, stiff foam; homogeneous by TLC in 3:1 hexane-EtOAc; mass spectrum (FAB) m/e 650 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.92 (t, J=7.3 Hz, 3H), 100 (s, 9H), 1.21 (t, J=7.5 Hz, 3H), 1.38 (m, 2H), 1.65 (m, 2H), 2.39 (q, J=7.5 Hz, 2H), 2.66 (t, J=7.8 Hz, 2H), 3.98 (s, 1H), 4.02 (s, 2H), 7.2-7.6 (m, 8H), 7.82 (d, J=2.5 Hz, 1H), 8.15 (dd, J=7.9, 1.4 Hz, 1H).
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[C:11]([OH:13])=[O:12].[N+]([O-])([O-])=O.[Na+].[I-:19].[K+].NC(N)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>Cl>[I:19][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[C:11]([OH:13])=[O:12]
Reactant: [I-]
Reactant: Nc1cccc(C(=O)O)c1C(=O)O
Agent: Cl
Agent: NC(N)=O
Agent: O=S([O-])([O-])=S
Product: O=C(O)c1cccc(I)c1C(=O)O
Reaction time: 3 h
Yield: 62 %

Procedure:
3-Aminophthalic acid (5.00 g, 27.6 mmol) was dissolved in 8.4 mol/L hydrochloric acid (60 mL), and the solution was added with an aqueous solution (10 mL) of sodium nitrate (2.0 g, 29 mmol) by drops under ice-cooling for 20 minutes, followed by stirring at the same temperature for 3 hours. Then, an aqueous solution (10 mL), in which potassium iodide (6.9 g, 41 mmol) and urea (291 mg) were dissolved, is added by drops to the mixture, followed by stirring at room temperature for 20 hours. The reaction mixture was added with 10% aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was washed with chloroform to obtain 3-iodophthalic acid (5.0 g, yield 62%).
Reaction SMILES: [CH3:1][N:2](C)[CH3:3].Cl.CNC.[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20](OCC)=[O:21])[O:19][C:15]=2[C:14]([F:25])=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]=1[CH3:32])#[N:10].Cl>ClCCl>[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([N:2]([CH3:3])[CH3:1])=[O:21])[O:19][C:15]=2[C:14]([F:25])=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]=1[CH3:32])#[N:10]
Reactant: CN(C)C
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reaction time: 0.42 h
Yield: 67 %

Procedure:
Under nitrogen atmosphere, trimethylamine (1.03 M n-hexane solution, 2.25 ml, 2.31 mmol) was dropwise added at room temperature to a dichloromethane (3 ml) solution of dimethylamine hydrochloride (189 mg, 2.31 mmol), followed by stilling for 25 minutes. Subsequently, a dichloromethane (2 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (250 mg, 771 μmol) was dropwise added, followed by stirring for 17 hours. After the reaction, aqueous 1N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature, and the reaction liquid was extracted with chloroform. Next, the obtained organic layers were combined, dried oil anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was suspended and washed in diethyl ether to obtain the entitled compound (167 mg, 67%) as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([OH:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6](O)[CH2:5][C:4]1=[O:57])[CH3:2].C(N(C(C)C)CC)(C)C.[N+](C1C=CC=CC=1S(Cl)(=O)=O)([O-])=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([OH:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]=[CH:5][C:4]1=[O:57])[CH3:2]
Reactant: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: CN(C)c1ccncc1
Agent: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC

Procedure:
To a solution of 404.5 mg of 17-ethyl-1,14,20-trihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone, 64.8 mg 4-dimethylaminopyridine, 87.1 μl of diisopropyl ethyl amine and 4 ml methylene chloride stirred magnetically at 0° C. was added 113.2 mg o-nitrophenylsulfonyl chloride in 2 ml methylene chloride. At 19 hours the mixture was evaporated and purified by thin layer chromatography on silica gel using hexane/acetone mixtures (60/40 and 50/50) as eluent. The faster moving compound, 155 mg, was repurified on silica gel preparative thin layer chromatography using ethyl acetate as eluent. The slower moving compound, 69.8 mg, was identified as 17-ethyl-1,20-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-14,18-diene-2,3,10,16-tetraone.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:30])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH3:30])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1ccccc1/C=C/C(=O)O
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccccc3C)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-o-tolyl-acrylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([C:28]([CH:30]2[CH2:32][CH2:31]2)=[O:29])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH3:34][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([C:28]([CH:30]2[CH2:32][CH2:31]2)=[O:29])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:34])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
{2′-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester (0.408 g, 0.88 mmol) was dissolved in THF (4 mL) and cooled to −78° C. Sodium bis(trimethylsilyl)amide (1M in THF; 1.06 mL, 1.06 mmol) was added, followed by iodomethane (0.06 mL, 0.97 mmol), and the reaction was stirred at −78° C. for 30 minutes. The mixture was quenched with saturated aqueous NH4Cl and warmed to room temperature. The mixture was extracted three times with EtOAc, and the combined organic layers were dried, concentrated, and purified by silica gel chromatography (10-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH:22]=[O:23].O>O1CCCC1>[OH:23][CH:22]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)[CH2:21][C:20]([CH3:25])([CH3:24])[CH3:19]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CC(C)(C)CC=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(O)CC(C)(C)C)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a −40° C. solution of methyl 4-iodobenzoate (1 g, 4 mmol) in tetrahydrofuran (10 mL) was added isopropylmagnesium chloride lithium chloride (3.82 mL, 1.3 M in THF, 4.98 mmol). The mixture was stirred at −40° C. for 30 minutes. 3,3-Dimethylbutanal (573 mg, 2.86 mmol) was added. The reaction was stirred at room temperature for 4 hours. Water (10 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave (+/−)-methyl 4-(1-hydroxy-3,3-dimethylbutyl)benzoate (640 mg, 95%). 1H NMR (400 MHz, CDCl3, δ): 7.93 (d, 2H), 7.34 (d, 2H), 4.81-4.84 (m, 1H), 3.84 (s, 3H), 1.70-1.61 (m, 1H), 1.53-1.49 (m, 1H), 0.94 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]1[O:13][CH2:14][C:15](=[O:22])[C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][N:30]=2)[C:25]([CH:32]=O)=[CH:24]1.N1CCCCC1>C(O)C>[NH:23]1[C:31]2=[N:30][CH:29]=[CH:28][CH:27]=[C:26]2[C:25]([CH:32]=[C:14]2[O:13][C:12]([NH:11][C:4]3[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=3[O:2][CH3:1])=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]2=[O:22])=[CH:24]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(OC)cc2OC)OCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccc(OC)cc2OC)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 27.1 %

Procedure:
To a solution of ethyl 2-[(2,4-dimethoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.35 g, 1.1 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.12 g, 1.1 mmol) in ethanol (10 mL), piperidine (0.5 mL, 4.6 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound (0.13 g, y. 26%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][C:18]#[C:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([Cl:24])(=[O:23])N>>[CH2:1]([N:8]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][C:18]#[C:19][CH3:20])[C:21]([Cl:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#COCCOCCOCCNCc1ccccc1
Reactant: NC(=O)Cl
Product: CC#COCCOCCOCCN(Cc1ccccc1)C(=O)Cl

Procedure:
N-Benzyl-2-(2-(2-(propynyloxy)ethoxy)ethoxy)ethyl aminocarbonyl chloride was prepared from amine 27 (20 mg, 0.072 mmol) following General Procedure 1. The crude carbamoyl chloride was used directly for the next step.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.Cl[CH2:14]CCC(C1C=CC=CC=1)=O>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[NH:1]1[C:2]2=[C:11]3[C:6](=[CH:5][CH:4]=[CH:3]2)[CH:7]=[CH:8][CH:9]=[C:10]3[NH:12][CH2:14]1
Reactant: Nc1cccc2cccc(N)c12
Reactant: O=C(CCCCl)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1cc2c3c(cccc3c1)NCN2
Yield: 47.4 %

Procedure:
A stirred mixture of 1.411 g of 1,8-diaminonaphthalene, 1.629 g of 4-chlorobutyro-phenone, 3 mg of p-toluenesulfonic acid monohydrate, and 10 mL of toluene was heated to reflux under a nitrogen atmosphere using a Dean-Stark trap to remove the water evolved from the reaction for 10 hr. The mixture was filtered to remove unreacted starting material, partioned between ethyl acetate and 5% sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 2.04 g of crude product. This was further purified by chromatography on silica gel, eluting with 1:1 diethyl ether/petroleum ether, and collecting the initial band to yield 0.719 g of dihydroperimidine intermediate.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:35]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][Br:35])[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(OC(=O)c2ccccc2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Oc1cccc(CBr)c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 20.83 g (0.098 mol) of 3-methylphenyl benzoate in 280 mL of carbon tetrachloride was added a catalytic amount of benzoyl peroxide, followed by 20.96 g (0.118 mol) of N-bromosuccinimide. The reaction mixture was stirred and heated under reflux overnight. After cooling to room temperature, the solid material was filtered off. The filtrate was washed with 100 mL of water. The organic phase was removed and dried over magnesium sulfate, filtered and evaporated to dryness in a rotary evaporator. The crude product (31.3 g) was purified by HPLC to give 20.61 g and was used directly in the next step.
Reaction SMILES: N[C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[C:24]([Cu])#[N:25].N(OC(C)(C)C)=O>CS(C)=O.[Cl-].[Na+].O>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[N:6]1[C:5]2[C:18]([C:20]([F:23])([F:21])[F:22])=[CH:19][C:2]([C:24]#[N:25])=[CH:3][C:4]=2[NH:8][C:7]1=[O:9]
Reactant: N#C[Cu]
Reactant: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccc(Cl)cc1Cl
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccc(Cl)cc1Cl
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 19.4 %

Procedure:
5-Amino-1-(2,4-dichlorophenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one (0.7860 g) was dissolved in dimethyl sulfoxide (35 ml), and to the solution was added CuCN (0.5551 g). The mixture was heated at 55° C. At the same temperature, t-butyl nitrite (0.761 ml) was added dropwise during 1.5 hours. After the addition was completed, the mixture was stirred at 60° C. for 1.5 hours. After allowing to cool, to the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (60 g, CHCl3:methanol=10:1) and then by silica gel column (70 g, hexane:ethyl acetate=1:1) to give the title compound (0.1570 g, 19%).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:38])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:37])[CH2:27][CH2:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32].[BH4-].[Na+]>CO>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:38])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:37])[CH2:27][CH2:28][CH2:29][C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34]
Reactant: CN(CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F)CCCC(F)(F)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F)CCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
380 mg of 11β-fluoro-3-hydroxy-7α-{5-[methyl-(4,4,5,5,5-pentafluoro-pentyl)-amino]-pentyl}-estra-1,3,5(10)-trien-17-one is dissolved in 25 ml of methanol and mixed with 77 mg of sodium borohydride. After 30 minutes of stirring at room temperature, the batch is added to saturated common salt solution, extracted with methylene chloride, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a methylene chloride-methanol gradient, 317 mg of 11β-fluoro-7α-{5-[methyl-(4,4,5,5,5-pentafluoro-pentyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol is obtained as a foam, [α]D=+49° (c=0.5 in methanol).