Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[Li]CCCC.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[CH2:28][CH2:27][CH2:26]2.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([C:2]1[CH:7]=[N:6][C:5]([O:8][CH2:9][CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1)([OH:33])[CH2:28][CH2:27][CH2:26]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: Brc1ccc(OCCN2CCCC2)nc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCCC2(O)c1ccc(OCCN2CCCC2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
To a solution of 5-Bromo-2-(2-pyrrolidin-1-ylethoxy)pyridine (7.0 g, 26 mmol) in dry THF (50 mL) at -78° C. was added n-BuLi (2.5 M in hexanes, 12.4 mL, 31.0 mmol) dropwise. After 30 min, 6-methoxy-1-tetralone (4.55 g, 25.8 mmol) in dry THF was added. After stirring for 15 min at -78° C., the reaction was allowed to warm to room temperature. After 30 min, the reaction was poured into aq NaHCO3 (satd). The aqueous layer was extracted with EtOAc (2×). The combined organic solutions were dried (MgSO4), filtered, and concentrated. Flash chromatography (CHCl3 :MeOH, 95:5) provided the alcohol (4.23 g, 44%) as a white solid. 1H NMR (250 MHz, CDCl3): δ8.07 (d, J=2.5 Hz, 1H), 7.49 (dd, J=2.5, 8.7 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 6.73 (m, 3H), 4.45 (t, J=5.7 Hz, 2H), 3.79 (s, 3H), 2.92 (t, J=5.7 Hz, 2H), 2.76 (m, 2H), 2.67 (m, 4H), 2.11 (s, 1H), 2.08 (m, 3H), 1.82 (m, 5H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:14]>O=S(Cl)Cl.C1COCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH2:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: O=C(O)CCCCC1CCCCC1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NC(=O)CCCCC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A solution of cyclohexanepentanoic acid (2 g, 10.9 mmol) in SOCl2 (8 mL) was heated on a steam bath for 3 h. The SOCl2 was removed under vacuum. Chloroform (2×10 mL) was added and reevaporated to give the crude acid chloride as a yellow liquid. A saturated solution of ammonia in dry THF (ammonia gas bubbled through 10 mL of THF for 5 min), was slowly added to a solution of the acid chloride in dry THF (50 mL) while cooling in an ice bath. The reaction mixture was allowed to stir at room temperature for 3 h and was then concentrated to half of its volume and poured onto water (100 mL). The solid was removed by filtration, washed with water and dried (MgSO4). Recrystallization from aqueous MeOH gave 5-cyclohexylvaleramide (1.1 g, 55%); mp 121-122° C. (reported mp 122-123° C.) (Katsellson and Dubinin, Compt. Rend. Acad. Sci. U.R.S.S. [N.S.] 4:405 (1936); Chem. Abstr. 31:3449 (1937)). A suspension of the amide (183 mg, 1 mmol) in anhydrous Et2O (9 mL) was slowly added to a stirred suspension of LiAlH4 (114 mg, 3 mmol) in Et2O (15 mL). After addition was complete, the mixture was heated at reflux for 2 h and then allowed to stir overnight at room temperature. The reaction mixture was cooled to 0° C. and excess LiAlH4 was decomposed by successive addition of water (2 mL), 2N NaOH (2 mL) and water (5 mL). After stirring vigorously for 20 min, the mixture was filtered and the inorganic residue was washed with warm Et2O (3×8 mL). The combined Et2O solution was dried over anhydrous K2CO3 and evaporated to dryness. The residue was distilled under reduced pressure to yield a clear oil (99 mg, 59%); bp 30-36° C. (0.35 mm), Lit. bp 108≥113° C. (15 nm) (Skinner, C. G., et al., J. Am. Chem. Soc. 79:2844 (1957)). A solution of the free base in anhydrous Et2O was added to a solution of oxalic acid (52 mg) in anhydrous Et2O (8 mL) with continuous shaking. The precipitated solid was recrystallized from MeOH/anhydrous Et2O; mp 164° C. (see Table 8).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:23]([NH2:26])[CH2:24][CH3:25]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([NH:26][CH2:23][CH2:24][CH3:25])[N:3]=1
Reactant: CCCN
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Solvent: COCCOC
Product: CCCNc1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N

Procedure:
From 2-amino-4-benzo[1,3 ]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and propylamine in DME. ES-MS m/e (%): 298 (M+H+, 100).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:25]1([CH2:31][CH2:32]O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([O:21][CH2:32][CH2:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: OCCc1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1OCCc1ccccc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 11.4 %

Procedure:
A solution of 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol (1.0 g, 3.08 mmol), 2-phenylethanol (414 mg, 3.39 mmol), triphenylphosphine (890 mg, 3.39 mmol) and diethyl azodicarboxylate (590 mg, 3.39 mmol) in tetrahydrofuran (20 mL) was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=100/1) to obtain the title compound (150 mg, yield 11%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:56]1[CH2:61][CH2:60][CH:59]([O:62][CH2:63][CH2:64][N:65]2[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]2)[CH2:58][CH2:57]1>CC(N(C)C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:56]1[CH2:61][CH2:60][CH:59]([O:62][CH2:63][CH2:64][N:65]2[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]2)[CH2:58][CH2:57]1)=[O:5]
Reactant: C1CCN(CCOC2CCNCC2)CC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OCCN2CCCCC2)CC1
Reaction time: 2 h
Yield: 20.9 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1)(0.20 g, 0.67 mmol) and HBTU (0.381 g, 1.01 mmol) were added to DMA (4 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and then 1-(2-(piperidin-4-yloxy)ethyl)piperidine (115) (0.214 g, 1.01 mmol). The reaction was stirred for 2 hours before being evaporated to dryness and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (0.069 g, 20.74% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.36-1.45 (2H, m), 1.64-1.94 (8H, m), 2.37-2.50 (4H, m), 2.55 (2H, t), 3.03-3.15 (1H, m), 3.37-3.49 (1H, m), 3.50-3.65 (4H, m), 3.92-4.04 (1H, m), 4.30 (2H, s), 7.00 (1H, t), 7.21-7.32 (2H, m), 7.68-7.79 (3H, m), 8.43-8.49 (1H, m), 10.49 (1H, s); m/z (LC-MS, ESI+), RT=2.01 (M+H 493.5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[Na+].[Na+].Cl.C[N:17]([CH2:21][CH2:22]Cl)[CH2:18][CH2:19]Cl>C(O)CCC>[N:1]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])[CH2:22][CH2:21][NH:17][CH2:18][CH2:19]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: Oc1ccccc1N1CCNCC1
Temperature: 123 °C

Procedure:
2-Aminophenol (6 g; 54 mmol) is dissolved in 1-butanol (110 ml) in the presence of sodium carbonate (2.9 g; 27.5 mmol) and N-methylbis(2-chloroethyl)amine hydrochloride (11.1 g; 58 mmol). The suspension is heated at 123° C. for 3 days. The butanol is evaporated off under reduced pressure and compound 43A is purified by flash chromatography with the following mixtures of eluents: NH4 OH/acetone/CH2Cl2 (0.5/20/80) and then NH4 OH/methanol/CH2Cl2 (1/5/95).
Reaction SMILES: [O:1](C1C=C(C=CC=1)C=O)C1C=CC=CC=1.[Na:16].[CH3:17][C:18]1([CH3:30])[C@@H:20]([CH:21]([Br:26])[C:22]([Br:25])([Cl:24])[Cl:23])[C@@H:19]1[C:27](Cl)=[O:28]>[Cl-].[Zn+2].[Cl-]>[Na:16].[CH3:17][C:18]1([CH3:30])[C@@H:20]([CH:21]([Br:26])[C:22]([Br:25])([Cl:24])[Cl:23])[C@@H:19]1[C:27]([O-:1])=[O:28]
Reactant: CC1(C)[C@@H](C(=O)Cl)[C@@H]1C(Br)C(Cl)(Cl)Br
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Agent: [Na]
Agent: [Zn+2]
Product: CC1(C)[C@@H](C(=O)[O-])[C@@H]1C(Br)C(Cl)(Cl)Br
Temperature: 20 °C
Reaction time: 17 h

Procedure:
A mixture of 8 g of 3-phenoxy-benzaldehyde and 15.5 g of 1R, trans 2,2-dimethyl-3-(1',2'-dibromo-2',2'-dichloroethyl)-cyclopropane-1-carboxylic acid chloride was warmed to obtain a homogeneous liquid and the mixture was cooled to 20° C. 0.150 g of anhydrous zinc chloride were added thereto and the mixture was stirred at 20° C. for 17 hours to obtain raw RS α-chloro-3-phenoxy-benzyl 1R, trans 2,2-dimethyl-3-(1',2'-dibromo-2',2'-dichloroethyl)-cyclopropane-1-carboxylate whose IR spectrum showed an absorption at 1750 cm-1 (carbonyl) andwhose RMN Spectrum showed the absence of an aldehydic proton.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[N+:17]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Product: O=c1[nH]c2ncccc2c2cc(NCc3cccc([N+](=O)[O-])c3)ccc12
Yield: 11.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (115 mg, 0.55 mmol) and 3-nitro-benzyl bromide (113 mg, 0.66 mmol) to provide 465 (22 mg, 11% yield) as a white powder. LC-MS (M+H=347, obsd.=347). 1H NMR (400 MHz, DMSO-D6) δ 8.47 (m, 2H), 8.13 (s, 1H), 8.05 (m, 2H), 7.74 (d, J=7.7 , 1H), 7.58 (t, J=7.9, 1H), 7.42 (d, J=2.0, 1H), 7.37 (dd, J=4.7, 7.8, 1H), 6.91 (dd, J=2.0, 8.7, 1H), 6.24 (s, 2H), 5.76 (s, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][S:8][C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][S:8]([C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)=[O:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCSc1cccc2nccn12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCCS(=O)c1cccc2nccn12
Yield: 17.9 %

Procedure:
To a solution of 5-[3-(acetyloxy)propylthio]imidazo[1,2-a]pyridine (1.00 g, 3.99 mmoles) in chloroform (25 ml) was added m-chloroperbenzoic acid (1.47 g, 5.96 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 1.5 hours. The reaction mixture was washed in turn with an aqueous 20% sodium bisulfite solution and an aqueous saturated sodium bicarbonate solution and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent:hexane/acetone (1:1)] to obtain 0.19 g of 5-[3-(acetyloxy)propylsulfinyl]imidazo[1,2-a]pyridine (Compound 177) (34.6%, yellow oily product) and 0.19 g of 5-(acetyloxy)propylsulfonyl]imidazo[1,2-a]pyridine (Compound 178) (16.5%, yellow oily product).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:16][C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([O:24]CC[Si](C)(C)C)[N:19]=3)=[C:14]([C:31]([NH2:33])=[O:32])[CH:13]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:16][C:15]([NH:17][C:18]3[CH:23]=[CH:22][NH:21][C:20](=[O:24])[N:19]=3)=[C:14]([C:31]([NH2:33])=[O:32])[CH:13]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2]
Reactant: CC(C)(C#N)c1ccc(-c2cc(C(N)=O)c(Nc3ccnc(OCC[Si](C)(C)C)n3)s2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C#N)c1ccc(-c2cc(C(N)=O)c(Nc3cc[nH]c(=O)n3)s2)cc1

Procedure:
5-[4-(1-Cyano-1-methylethyl)phenyl]-2-({2-[2-(trimethylsilyl)ethoxy]pyrimidin-4-yl}amino)thiophene-3-carboxamide (107 mg, 0.223 mmol) was stirred in a mixture of DCM (5 mL) and TFA (2 mL) at room temperature for 30 minutes. Saturated NaHCO3 was added and the resulting precipitate collected by filtration and washed with water and DCM to give the title compound as a yellow solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:34]=[CH:35][CH:36]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([CH2:16][O:17][C:18]3[CH:31]=[CH:30][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:20][CH:19]=3)[N:13]([CH3:32])[C:12]=2[CH:33]=1.[CH2:37]([N:43]=[C:44]=[O:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C(N(CC)CC)C>CN(C)C=O>[O:28]=[C:26]1[NH:25][C:24](=[O:29])[CH:23]([CH2:22][C:21]2[CH:30]=[CH:31][C:18]([O:17][CH2:16][C:14]3[N:13]([CH3:32])[C:12]4[CH:33]=[C:8]([O:7][C:6]5[CH:5]=[C:4]([NH:3][C:44]([NH:43][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:45])[CH:36]=[CH:35][CH:34]=5)[CH:9]=[CH:10][C:11]=4[N:15]=3)=[CH:19][CH:20]=2)[S:27]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(N)c3)cc21
Reactant: CCCCCCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCNC(=O)Nc1cccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 67.8 %

Procedure:
A mixture of 5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), n-hexyl isocyanate (280 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 7 hours and then allowed to stand overnight. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate/n-hexane=3:1→4:1→ethyl acetate→ethyl acetate:methanol=15:1 as the eluant. The product was recrystallized from ethyl acetate to afford the title compound (298 mg, mp 143.7-146.9° C.).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].N1C=CC=CC=1.[CH3:12][N:13]([CH2:15][CH:16]1[CH2:25][C:24]2[C:19](=[CH:20][C:21]([NH:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:31][CH:30]=3)=[O:28])=[CH:22][CH:23]=2)[NH:18][CH2:17]1)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:14][N:13]([CH2:15][CH:16]1[CH2:25][C:24]2[C:19](=[CH:20][C:21]([NH:26][C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:33][CH:34]=3)=[O:28])=[CH:22][CH:23]=2)[N:18]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17]1)[CH3:12]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)CC1CNc2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)CC1Cc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc2N(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.02 ml) was added to pyridine solution (1 ml) of N-[3-[(N,N-dimethylamino)methyl]-1,2,3,4-tetrahydro-7-quinolinyl]-4-biphenylcarboxamide (80 mg) under ice-cooling, which was stirred at room temperature for 1 hour. Further, methanesulfonyl chloride (0.02 ml) was added to the reaction mixture under ice-cooling, which was stirred at room temperature for 12 hours. 10% aqueous potassium carbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was recrystallized using THF-IPE to give the titled compound (64 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29](=[O:33])[CH2:30][CH2:31][CH3:32]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([O:15][CH2:28][C:29](=[O:33])[CH2:30][CH2:31][CH3:32])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCCC(=O)CBr
Reactant: Cc1cn2c3ccc(Br)cc3c3cc(O)cc(c1=O)c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCC(=O)COc1cc2c(=O)c(C)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
10-bromo-2-hydroxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (250 mg) obtained in Example 49 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (210 mg) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and 1-bromo-2-pentanone (188 mg) was added to the mixture. The mixture was stirred at room temperature for 12 hours, and the reaction mixture was poured into ice water (500 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride containing 2% methanol) to obtain the title compound (150 mg, 48%).
Reaction SMILES: [H][H].[F:3][C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C:5]1=[O:23])[C@:18]1([CH3:19])[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]1)[CH2:12][CH2:11]3.CO.[OH-].[K+]>C(O)C.[Pd]>[F:3][C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C:5]1=[O:23])[C@:18]1([CH3:19])[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]1)[CH2:12][CH2:11]3
Reactant: [H][H]
Reactant: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@@H](F)C[C@@H]12
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@H](F)C[C@@H]12

Procedure:
250 mg of 16βfluoro-5-α-androsten-17-one in 50 ml of ethanol was treated with 50 mg of 5% palladium on carbon and hydrogen gas for 21/2 hours. The reaction mixture, as indicated by the IR, is compatible with 16β-fluoro-5α-androstan-17-one. This crude product was treated with 5 ml methanol and 5 ml of 1N methanolic KOH for one hour. The mixture was partitioned between methylene chloride and water and subjected to HPLC as indicated above. Crystallization of the less mobile component from methanol gave 30 mg of 16α-fluoro-5α-androstan-17-one as prismatic needles, melting point 148°-150° C.
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CN(C1C=CC=CN=1)[CH:19]=[O:20]>C1COCC1.C(OCC)C.C1COCC1>[C:1]1([C:7]2[O:11][C:10]([CH:19]=[O:20])=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C=O)c1ccccn1
Reactant: c1ccc(-c2cnco2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ncc(-c2ccccc2)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
According to reference (Synthesis 1984, 1048–1050), to a solution of 5-phenyloxazole (1.5 g, 10.3 mmol) in THF:diethyl ether (2:1, 50 mL) at −78° C. is added n-butyl lithium (7.1 mL of 1.6 M solution in hexanes, 11.4 mmol). The reaction is stirred at −78° C. for 30 minutes after which time a solution of N-methyl-2-pyridyl formamide (1.85 mL, 15.5 mmol) in THF (20 mL) is added. The reaction mixture is stirred at −78° C. for 30 min and then at 25° C. for 14 hours. It is quenched by addition of water and extracted with ethyl acetate. The combined organic layers are washed with 10% HCl, saturated sodium bicarbonate and brine before being dried over sodium sulfate and concentrated. The resulting oil is purified by column chromatography (5% ethyl acetate in hexanes) to afford 246 ng of 5-phenyl-1,3-oxazole-2-carbaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][C@H:10]2[CH2:14][O:13]C(C)(C)[O:11]2)=[CH:5][CH:4]=1>CC(O)=O.O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][C@H:10]([OH:11])[CH2:14][OH:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(OCC[C@H]2COC(C)(C)O2)cc1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(OCC[C@H](O)CO)cc1

Procedure:
A solution of (4S)-4-[2-(4-methoxyphenoxy)ethyl]-2,2-dimethyl-1,3-dioxolane (8.2 g, 30.8 mmol) in AcOH/water was stirred at rt for 5 h and concentrated in vacuo. The residue was co-evaporated with toluene (3×) and then pumped under high vacuum to give the desired product.
Reaction SMILES: [CH2:1]([C@H:3]1[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:5]=2[O:4]1)[CH3:2].S(Cl)([Cl:22])=O>>[CH2:1]([C@H:3]1[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][C:15]([C:17]([Cl:22])=[O:19])=[CH:16][C:5]=2[O:4]1)[CH3:2]
Reactant: CC[C@@H]1Oc2cc(C(=O)O)ccc2N(C(C)C)C1=O
Reactant: O=S(Cl)Cl
Product: CC[C@@H]1Oc2cc(C(=O)Cl)ccc2N(C(C)C)C1=O

Procedure:
A mixture of (S)-2-ethyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxylic acid (0.70 g) in thionyl chloride (15 ml) was stirred under reflux for 2 hours. Thionyl chloride was distilled off under reduced pressure to give (S)-2-ethyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carbonyl chloride (0.70 g).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]([CH:7]([C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[CH3:8])=[O:6]>CO.Cl.[Pd]>[CH3:17][C:2]([CH3:1])([CH3:18])[CH2:3][NH:4][C:5]([CH:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH2:14])=[CH:15][CH:16]=1)[CH3:8])=[O:6]
Reactant: CC(C(=O)NCC(C)(C)C)c1ccc(C#N)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C(=O)NCC(C)(C)C)c1ccc(CN)cc1
Yield: 84.2 %

Procedure:
Bubble nitrogen into a solution of (±)-4-[1-(2,2-dimethylpropyl-carbamoyl)-ethyl]-benzonitrile (80 mg, 0.33 mmol) in methanol (9 mL) with 2 drops of concentrated HCl for 10 min. Add 10% Pd/C (Degussa type E101, 8 mg) and submit the mixture to hydrogenation at atmospheric pressure overnight. Filter the catalyst over Celite® and concentrate the filtrate in vacuo. Partition the solid between saturated aqueous NaHCO3 and EtOAc, and extract again with EtOAc. Dry the combined organics extracts over MgSO4, filter and concentrate in vacuo to afford the title compound as a yellow oil (69 mg, 85%). MS (ES+) m/z: 249 (M+H)+.