Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[CH2:1]([O:16][C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.4 %

Procedure:
This was prepared as follows:- A solution of benzyl bromide (10.26 g; 60 mmol) and 4chloro-3-nitrophenol (8.7 g; 50 mmol) in DMF (250 ml) was treated with Na2CO3 (10.6 g; 0.1 mol) and the mixture was stirred at room temperature for 3 days. The mixture was poured into water and extracted with Et2O. The organic phase was washed with brine and dried over MgSO4. The residue was purified by flash chromatography eluting with CH2Cl2 to give 5-benzyloxy-2-chloro-nitrobenzene as a pale yellow solid (12.32 g).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[CH2:21]([CH:18]([N:13]1[C:12]([C:35]2[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH2:19][CH3:20])[CH3:22]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCC(CC)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCC(CC)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Yield: 93.7 %

Procedure:
The title compound (93 mg) was prepared as in Example 177, Steps C and D, using 150 mg of 2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 138 mg of 3-fluorophenylboronic acid. MS (ESI): exact mass calculated for C18H24FN3, 301.20. found, m/z 302.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.44-7.30 (m, 4H), 3.92-3.85 (m, 1H), 3.51-3.43 (m, 2H), 3.38-3.33 (m, 2H), 3.30-3.24 (m, 2H), 2.86-2.78 (m, 2H), 1.98-1.85 (m, 2H), 1.84-1.73 (m, 2H), 0.73 (t, J=7.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12]O.S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:16][CH2:12][C:3]1[C:2]([F:1])=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH2:7][CH2:8][CH2:9][CH2:10]2
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2c(c1F)CCCC2
Solvent: ClCCl
Product: Fc1c(CCl)ccc2c1CCCC2

Procedure:
The alcohol 47.7 (0.5 g, 2.77 mmol) is dissolved in anhydrous DCM (50 mL). Thionyl chloride (302 μL, 4.2 mmol) is slowly added dropwise to the above solution. The resulting mixture is stirred until TLC confirms the consumption of the starting material. The organic solvent is removed in vacuo. The residue is purified by column chromatography (silica, EtOAc/Hexane), to afford chloride 47.8.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1([C:28](O)=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:28]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)C1CCCc2ccccc21
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CCCc5ccccc54)cc23)CC1

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole with 16.2 mg (0.10 mMol) 1,2,3,4-tetrahydro-1-naphthoic acid at 70° C., 16.2 mg (84%) of the title compound were recovered.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]([C:7]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:9])[C:5]=1[C:10]([NH:1][C:4]1[CH:14]=[CH:13][CH:12]=[CH:6][CH:5]=1)=[O:11])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Product: O=C(Nc1ccccc1)c1cccc([N+](=O)[O-])c1C(=O)Nc1ccccc1

Procedure:
50 g (259 mmol) 3-nitro-phtalic anhydride and 24.7 g (24.1 mL, 266 mmol) aniline in 710 mL acetic acid were heated to reflux for 3 hours under an argon atmosphere. Acetic acid was removed under reduced pressure and the residue was treated with 150 mL ethanol at 0° C. The precipitated 3-nitro-phtalanilide was isolated by filtration, washed with a small amount of cold ethanol and dried. 59.1 g (58%) 3-nitro-phtalanilide was isolated (m.p. 139-141° C.)
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:31]1([NH:34][C:23](=[O:25])[C:22]2[CH:26]=[CH:27][C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][CH2:30][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:14][CH2:15]3)=[CH:20][CH:21]=2)[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.9 %

Procedure:
(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (87 mg, 0.214 mmol) and cyclopropanamine (18.29 mg, 0.320 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.068 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.427 mmol). The reaction mixture was stirred at room temperature for 3 h and purified using HPLC (25-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)—N-cyclopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (43.0 mg, 0.096 mmol, 45.1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.46-0.59 (m, 2 H) 0.59-0.71 (m, 2 H) 1.82-2.02 (m, 3 H) 2.10-2.25 (m, 1 H) 2.46 (br. s., 4 H) 2.74-2.83 (m, 1 H) 3.21 (br. s., 4 H) 3.34-3.46 (m, 3 H) 3.53-3.64 (m, 1 H) 3.94-4.02 (m, 1 H) 6.91 (d, J=8.84 Hz, 2 H) 6.98 (d, J=1.77 Hz, 1 H) 7.61 (d, J=1.26 Hz, 1 H) 7.68 (d, J=8.84 Hz, 2 H) 8.13 (d, J=4.04 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C25H30N6O2, 447; found, 447; melting point 265-268° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=[C:11]([Cl:12])[C:4]=2[N:3]=1.[Cl:17][C:18]1[CH:24]=[C:23]([CH3:25])[C:21]([NH2:22])=[C:20]([O:26][CH3:27])[CH:19]=1.C(=O)([O-])O.[Na+]>>[Cl:12][C:11]1[C:4]2[N:3]=[C:2]([NH:22][C:21]3[C:23]([CH3:25])=[CH:24][C:18]([Cl:17])=[CH:19][C:20]=3[O:26][CH3:27])[N:6]([CH3:7])[C:5]=2[C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=1
Reactant: COc1cc(Cl)cc(C)c1N
Reactant: COC(=O)c1ccc(Cl)c2nc(Cl)n(C)c12
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(C)c12
Temperature: 130 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
A mixture of methyl 2,4-dichloro-1-methyl-1H-benzimidazole-7-carboxylate (100 mg, 0.39 mmol) and 4-chloro-2-methoxy-6-methylaniline (200 mg, 1.17 mmol) was stirred at 130° C. overnight. After cooling, the reaction mixture was neutralized by aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organics was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on a silica gel column to give 68 mg (0.17 mmol, 44%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][S:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[NH:11]2)=[CH:4][C:3]=1[O:26][CH3:27].Br[CH:29](Br)[CH3:30].C(N(CC)CC)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:30][CH2:29][N:11]3[CH:10]([CH2:15][S:14][CH2:13][CH:12]3[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH2:9]2)=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: CC(Br)Br
Reactant: COc1cc(NCC2CSCC(c3ccc(OC)c(OC)c3)N2)ccc1Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1cc(N2CCN3C(CSCC3c3ccc(OC)c(OC)c3)C2)ccc1Cl
Temperature: 90 °C
Reaction time: 4 h
Yield: 31.9 %

Procedure:
A solution of (4-chloro-3-methoxy-phenyl)-[5-(3,4-dimethoxy-phenyl)-thiomorpholin-3-ylmethyl]-amine (100 mg, 0.245 mmol, 1.0 equivalents), dibromoethane (0.31 ml, 3.55 mmol, 14.5 equivalents) and triethylamine (0.15 ml, 1.09 mmol, 4.5 equivalents) in dimethylacetamide (2 ml) was heated at 90° C. for 4 hours. Additional dibromoethane (0.16 ml, 1.84 mmol, 7.5 equivalents) and triethylamine (0.25 ml, 1.76 mmol, 7.2 equivalents) was added and reaction was stirred for 4 hours at 90° C. Additional dibromoethane (0.14 ml, 1.62 mmol, 6.6 equivalents) and triethylamine (0.10 ml, 0.71 mmol, 2.9 equivalents) were added and reaction was stirred 18 hours at 90° C. Reaction was cooled and filtered to remove triethylammonium hydrobromide. Filtrate was concentrated. Residue was purified on a 1000 micron preparative TLC. 34 mg of 8-(4-chloro-3-methoxy-phenyl)-4-(3,4-dimethoxy-phenyl)-octahydro-pyrazino[2,1-c][1,4]thiazine (Compound 8) was obtained, along with 36 mg recovered starting material. Yield of product: 32%. H1 NMR (400 MHz, CDCl3): 7.19 (1H, d), 6.86 (3H, m), 6.42 (2H, m), 3.89 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.50 (1H, m), 3.19 (2H, dd), 2.92 (1H, m), 2.75 (5H, m), 2.48 (2H, t), 2.15 (1H, dt). MS (LC-MS): Calculated for C22H27ClN2O3S 435.14, 435.24. IX. 2-(4-Chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine Via Scheme H
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=O)[CH:17]([O:21]CC)OCC)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[NH2:25][C:26]1[C:35]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:34][C:33]2[C:32]3[CH:43]=[CH:44][C:45]([OH:47])=[CH:46][C:31]=3[CH:30]=[CH:29][C:28]=2[N:27]=1.Cl>C(O)C.O>[CH:40]1[CH:39]=[CH:38][C:37]([CH2:36][C:35]2[NH:34][C:33]3[C:32]4[CH:43]=[CH:44][C:45]([OH:47])=[CH:46][C:31]=4[CH:30]=[CH:29][C:28]=3[N:27]3[C:26]=2[N:25]=[C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:17]3=[O:21])=[CH:42][CH:41]=1
Reactant: CCOC(OCC)C(=O)Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: Nc1nc2ccc3cc(O)ccc3c2nc1Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1c(Cc2ccc(O)cc2)nc2c(Cc3ccccc3)[nH]c3c4ccc(O)cc4ccc3n1-2
Temperature: 0 °C
Reaction time: 18 h
Yield: 13.3 %

Procedure:
Under an argon atmosphere, to a solution of 3-(4-(tert-butyldimethylsilyloxy)phenyl)-1,1-diethoxypropan-2-one (15) (101 mg, 286 μmol) in ethanol (2 mL) and water (0.4 mL) was added 3-amino-2-benzylbenzo[f]quinoxalin-8-ol (14) (55.5 mg, 184 μmol). After cooling to 0° C., to the mixture was further added conc. hydrochloric acid (0.20 mL). The mixture was heated to 80° C. and stirred overnight (18 hours). After cooling to room temperature and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=1/1→1/2→ethyl acetate alone) in an argon flow to give v-coelenterazine (2, v-CTZ) (10.9 mg, 24.4 μmol, 13.2%) as ocherous powders. TLC Rf=0.50 (n-hexane/ethyl acetate=1/1); 1H NMR (500 MHz, CD3OD) δ 4.08 (s, 2H), 4.51 (s, 2H), 6.69-6.72 (AA′BB′, 2H), 7.17-7.24 (m, 5H), 7.29 (t, 2H, J=7.5 Hz), 7.43 (d, 2H, J=7.5 Hz), 7.63 (d, 1H, J=8.5 Hz), 8.40 (br, 1H), 9.26 (br, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH2:12][OH:13])[N:11]=[C:4]2[N:3]=1>ClCCCl.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH:12]=[O:13])[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(CO)nc2n1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(C)n2nc(C=O)nc2n1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A slurry of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-methanol (0.3 g, 1.7 mmol) from Step 2 above and IBX (1.4 g, 5.0 mmol) in 1,2-dichloroethane (22 mL) was stirred at 80° C. for 18 hours. The reaction was cooled to room temperature, and diluted with 100 mL CH2Cl2. After the solids were removed by filtration, the solvent was removed by rotary evaporation to give a yellow solid. The solid was purified by flash chromatography to give the desired product (229 mg, 77% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C(O)C>[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CCCN1CCCCBr
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CCCN1CCCCN1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-bromobutyl)-2-pyrrolidinone (2.0 g/9.1 mmol) and benzylpiperazine (1.58 ml/9.1 mmol) in ethanol (4.5 ml) was stirred overnight at ambient temperature. The mixture was basified with 2 N NaOH and extracted with dichloromethane (50 ml×2). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (100 g/dichloromethane=100:5-100:10) to give a pale yellow oil (1.6 g/56%).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([NH2:20])=O)[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH2:23][CH3:24])([C:10]2=[O:21])[CH2:8][CH2:7][C:6](=[O:25])[CH:5]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]#[N:20])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH2:23][CH3:24])([C:10]2=[O:21])[CH2:8][CH2:7][C:6](=[O:25])[CH:5]=1
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OCC(N)=O)c(Cl)c1Cl)C2=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC12CCC(=O)C=C1c1c(cc(OCC#N)c(Cl)c1Cl)C2=O

Procedure:
[(5,6-Dichloro-3,9-dioxo-9a-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetamide (3.65 g, 10 mMole) is dissolved in pyridine (25 ml) and N,N'-dicyclohexylcarbodiimide (2.17 g, 10.5 mMole) in pyridine (15 ml) is added portionwise over 30 minutes with stirring at 15°-20° C. The mixture is then stirred at ambient temperature for 3 hours. The precipitated dicyclohexylurea is removed by filtration and the pyridine removed from the filtrate by evaporation in vacuo. Addition of water to the residue gives the product which is dissolved in methylene chloride, dried over MgSO4 and the solvent removed to provide the [(5,6-dichloro-3,9-dioxo-9a-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetonitrile.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20]N1C(=O)CCC1=O.O[C@H:29]1[CH2:46][CH2:45][C@@:44]2([CH3:47])[C@@H:31]([CH2:32][CH2:33][C@@H:34]3[C@@H:43]2[CH2:42][CH2:41][C@@:39]2([CH3:40])[C@H:35]3[CH2:36][CH2:37][C@@H:38]2[O:48][CH3:49])[CH2:30]1.CO>C1COCC1>[Cl:20][C@@H:29]1[CH2:46][CH2:45][C@@:44]2([CH3:47])[C@@H:31]([CH2:32][CH2:33][C@@H:34]3[C@@H:43]2[CH2:42][CH2:41][C@@:39]2([CH3:40])[C@H:35]3[CH2:36][CH2:37][C@@H:38]2[O:48][CH3:49])[CH2:30]1
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](Cl)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 2 h

Procedure:
A solution of triphenylphosphine (8.22 g.) in THF (80 ml.) is added dropwise to N-chlorosuccinimide (4.18 g.) with stirring and cooling so that the temperature remains below 30°. A solution of 3β-hydroxy-17β-methoxy-5α-androstane (Example 27, 4.8 g.) in THF (50 ml.) is slowly added to the N-chlorosuccinimide mixture. After 2 hours, methanol is added and the mixture is filtered to obtain the title compound (recrystallized from acetone): m.p. 151°-154°; NMR (CDCl3) 0.74, 0.78, 3.20, 3.33 and 4.47 δ; MS (m/e) 324, 309, 277 and 251.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[CH:9][CH:8]=3.[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25].C(Cl)Cl.[Cl-].[NH4+]>C(N(CC)CC)C.[Cu](I)I>[CH3:27][Si:26]([C:24]#[C:25][C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[CH:9][CH:8]=3)([CH3:29])[CH3:28]
Reactant: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(Br)cnc12
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Temperature: 90 °C
Yield: 75 %

Procedure:
To a suspension of 3-{[1-bromo-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4-yl]amino}propan-1-ol as prepared in example 2 (100 mg, 0.26 mmol), ethynyltrimethylsilane (81 μL, 0.57 mmol) and copper iodide (5 mg, 0.026 mmol) in anhydrous triethylamine (3.5 mL) degassed under argon for 10 minutes was added Pd(dppf)Cl2.DCM (11 mg, 0.013 mmol). The mixture was stirred at 90° C. for 1 h45 and then allowed to cool to room temperature, poured onto a saturated aqueous solution of ammonium chloride and extracted three times with ethyl acetate/tetrahydrofuran (1:1). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC (silica gel, dichloromethane/methanol 20/1) to afford the title compound (80 mg, 75%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:16]=[CH:15][C:14](I)=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[F:20][C:21]([F:26])([F:25])C([O-])=O.[Na+].O.ClCCl>CN1CCCC1.[Cu]I>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:16]=[CH:15][C:14]([C:21]([F:26])([F:25])[F:20])=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: COC(=O)c1cc(I)cnc1Oc1ccc(F)cc1
Agent: [Cu]I
Agent: CN1CCCC1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(C(F)(F)F)cnc1Oc1ccc(F)cc1
Temperature: 160 °C
Reaction time: 16 h
Yield: 10.2 %

Procedure:
A mixture of methyl 2-(4-fluorophenoxy)-5-iodonicotinate (step 1, 373 mg, 1.0 mmol), sodium trifluoroacetate (1.36 g, 10 mmol), and copper(I) iodide (960 mg, 5.0 mmol) in 1-methyl-pyrolidine (8.0 mL) was stirred at 160° C. for 16 h under nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extacted with dichloromethane (50 mL×3). The combined organic extracts were washed with brine (50 mL) and dried (sodium sulfate). After removal of the solvent, the residue was purified by TLC plate developing with hexane/ethyl acetate (1/1) to afford 32 mg (10%) of the title compound: 1H-NMR (CDCl3) δ 8.5 (2H, s), 7.13 (1H, d, J=6.3 Hz), 3.99 (3H, s); MS (ESI) m/z 316 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[F-].[K+].[SH:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[S:16][CH2:17][CH2:18][OH:19])([O-:3])=[O:2]
Reactant: OCCS
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(SCCO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 500 parts of 2,4-dinitro-1-chlorobenzene in 590 parts of N,N-dimethylformamide (DMF) are added 217 parts of potassium fluoride and the reaction mixture is stirred at room temperature for 5 hours. Then 350 parts of 2-mercaptoethanol are added dropwise, the internal temperature rising to 60°-65 ° C., and the reaction mixture is subsequently stirred at that temperature for about 15 hours. Starting materials still present are then made to react by adding 34 parts of potassium carbonate. Finally the reaction mixture is allowed to cool down to room temperature, salts are filtered off, and the filtrate is concentrated. The oily crude product is discharged onto water, and a yellow, crystalline precipitate forms. Filtering off with suction, washing and drying leaves 2-[2,4-dinitrophenylsulfanyl]ethanol in almost quantitative yield and high purity.
Reaction SMILES: [Na].[CH3:2][O-:3].[Na+].Cl[C:6]1[CH:11]=[C:10]([CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[N:9]=[C:8]([S:24][CH3:25])[N:7]=1>CO>[CH3:2][O:3][C:6]1[CH:11]=[C:10]([CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[N:9]=[C:8]([S:24][CH3:25])[N:7]=1
Reactant: CSc1nc(Cl)cc(CN2C(=O)c3ccccc3C2=O)n1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1cc(CN2C(=O)c3ccccc3C2=O)nc(SC)n1

Procedure:
To 100 ml of methanol was added 1.55 g (67.4 mmole) of sodium metal to prepare 67.4 mmole of sodium methoxide. To this solution was added 20.0 g (62.6 mmole) of 4-chloro-2-methylthio-6-phthalimidomethylpyrimidine (from Example 2) and the mixture was heated at reflux for 16 hours. The mixture was cooled, and the solid was then separated by filtration. This solid was washed sequentially with methanol and water to provide 4-methoxy-2-methylthio-6-phthalimidomethylpyrimidine as a white solid. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:19]=2)=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:34])=[CH:10][C:11]=2[Cl:33])[NH:6]1)=[O:4].[OH-].[Li+]>O1CCCC1.O>[C:3]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH:19]=2)=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:34])=[CH:10][C:11]=2[Cl:33])[NH:6]1)([OH:4])=[O:2]
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)c2cccc(CNC(=O)OC(C)(C)C)c2)c2c(Cl)cc(Cl)cc2N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cccc(C(=O)N[C@H]2C[C@H](C(=O)O)Nc3cc(Cl)cc(Cl)c32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of trans-2-methoxycarbonyl-5,7-dichloro-4-(3-tert-butyloxycarbonylaminomethylphenyl)carbonylamino-1,2,3,4-tetrahydroquinoline (step b) (430 mg, 0.846 mmol) in a mixture of tetrahydrofuran (20 ml) and water (10 ml) was added aqueous lithium hydroxide (1.95 ml of a 0.5M solution, 0.973 mmol), and the resulting mixture was stirred at room temperature for 3 h. The organic solvent was removed in vacuo and the aqueous residue was diluted to 50 ml before acidifying to pH 1 with 1N HCl. The white precipitate was extracted into ethyl acetate (150 ml), washed with brine and dried (Na2SO4). The solution was evaporated to give a residue which was washed with diethyl ether and collected by filtration to give the title compound as a colourless crystalline solid, m.p. 192°-193° C. δ (DMSO, 360 MHz) 1.39 (9H, s, C(CH3)3, 1.73 (1H, ddd, 13.2, 13.0 and 3.8 Hz, CHACHBHCCHD), 2.26 (1H, dm, J=13.2 Hz, CHACHBHCCHD), 3.96 (1H, dd, J=13.0 and 3.0 Hz, CHACHBHCCHD), 4.14 (2H, d,J=5.6 Hz, ArCH2NH), 5.26 (1H, m, CHACHBHCCHD), 6.65 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.82 (1H, br s, ArNHCO), 6.91 (1H, d, J=2.0 Hz, 6-H or 8-H). 7.36-7.37 and 7.72-7.76 (5H, m, Ar-H and CH2NHCO), 8.66 (1H, d, J=7 Hz, NHCOAr); m/e (FAB+), 494 (M+1), 93 (100%); Found C, 55.92; H, 5.22; N, 8.35; C23H25Cl2N3O5 requires C, 55.88; H, 5.10; N, 8.50%.