Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].C([O:9][C:10]([C:12]1[S:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]2)=[N:15][N:16]=1)=O)C>>[CH2:1]([NH:6][C:10]([C:12]1[S:13][C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[CH2:21][CH2:22]2)=[N:15][N:16]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Reactant: CCCCCN
Product: CCCCCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use n-pentylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.85 g, yield 77%). 1H NMR (300 MHz, CDCl3) δ 7.70-7.73 (m, 1H), 7.51-7.64 (m, 2H), 7.29-7.35 (m, 1H), 6.97-7.06 (m, 1H), 3.99-4.10 (m, 1H), 3.81-3.92 (m, 1H), 3.62-3.70 (m, 2H), 3.48-3.56 (m, 2H), 3.29-3.44 (m, 4H), 1.50-1.63 (m, 2H), 1.26-1.38 (m, 4H), 0.83-0.91 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 174.6, 167.6, 158.3, 156.1, 133.1, 132.5, 129.7, 127.7, 126.9, 125.4, 121.8. MS (ES+) m/z 455.9 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:10]=3[NH:11][C:12](=[O:15])[CH2:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].C(=[NH:43])(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:43][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:10]=3[NH:11][C:12](=[O:15])[CH2:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN=C(c2cccc(Br)c2)c2ccc3ccccc3c2N1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Nc1cccc(C2=NCC(=O)Nc3c2ccc2ccccc32)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
5-(3-Bromophenyl)-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one (50 mg, 0.14 mmol) was dissolved in tetrahydrofuran (5 mL), the solution was added with sodium tert-butoxide (26 mg, 0.27 mmol), benzophenone imine (46 μL, 0.27 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (5 mg, 8 μmol), and tris(dibenzylideneacetone)dipalladium (8 mg, 8 μmol), and the mixture was refluxed by heating for 5 hours under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, the residue was added with methanol (1 mL) and 2 M hydrochloric acid (3 mL), and the mixture was stirred at room temperature for 10 minutes. The mixture was added with saturated aqueous sodium hydrogencarbonate, and extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (30 mg, yield 71%) as yellow amorphous.
Reaction SMILES: C1O[C@@H]2[C@@H]([O:9][N+:10]([O-:12])=[O:11])CO[C@@H]2[C@@H]1O.C1O[C@@H]2[C@@H](O)CO[C@@H]2[C@@H]1O.[C:24]([O:27][C:28](=[O:30])[CH3:29])(=[O:26])[CH3:25]>>[N+:10]([O-:12])([OH:11])=[O:9].[C:24]([O:27][C:28](=[O:30])[CH3:29])(=[O:26])[CH3:25]
Reactant: O=[N+]([O-])O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Agent: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])O

Procedure:
The following process for preparing 1,4:3,6-dianhydro-D-glucitol 2-nitrate is described: acylating 1,4:3,6-dianhydro-D-glucitol with 0.5 to 1.5 molar equivalents of acetic anhydride in the presence of an acid catalyst, nitrating the product so obtained with a mixture of nitric acid and acetic anhydride, hydrolyzing the product so obtained in the presence of an inorganic base and isolating 1,4:3,6-dianhydro-D-glucitol 2-nitrate. The 1,4:3,6-dianhydro-D-glucitol 2-nitrate is useful as a coronary vasodilator.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.[CH3:15][C:16]1[C:17]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:26]2[CH2:27][CH2:28][N:23]([C:17]3[C:16]([CH3:15])=[CH:21][C:20]([CH3:22])=[CH:19][N:18]=3)[CH2:24][CH2:25]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 68.4 %

Procedure:
Using 4-bromo-2-methanesulfonylbenzoic acid (2.79 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (1.91 g) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (3.09 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.C(N(CC)C(C)C)(C)C.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](Cl)=[O:40]>ClCCl>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:39](=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Reactant: O=C(Cl)c1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NC(=O)c1ccccn1)N2
Temperature: 0 °C
Yield: 55.7 %

Procedure:
To an ice-cold mixture of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (60 mg, 0.19 mmol, 1.0 eq.) and N,N-diisopropylethylamine (50 mg, 0.38 mmol, 2.0 eq.) in 4 mL of dichloromethane was added dropwise a solution of picolinoyl chloride (40 mg, 0.29 mmol, 1.5 eq.) in dichloromethane (1 mL). Then the resultant mixture was stirred at room temperature for 30 min. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=2:1) to afford 44 mg of methyl 3,3-dimethyl-2-(2-(picolinamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a gray solid; yield: 60%. MS (ESI+APCI) M+1=416.2.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:43][CH3:44])=[C:35]([O:38][CH2:39][CH2:40][O:41][CH3:42])[CH:36]=2)[N:31]=[CH:30][N:29]=1>O1CCCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:28]3[C:37]4[C:32](=[CH:33][C:34]([O:43][CH3:44])=[C:35]([O:38][CH2:39][CH2:40][O:41][CH3:42])[CH:36]=4)[N:31]=[CH:30][N:29]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1cc2c(Cl)ncnc2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COCCOc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (223 mg, 0.83 mmol) was treated with cesium carbonate (325 mg, 1.0 mmol) in anhydrous tetrahydrofuran (8 mL). The mixture was stirred at room temperature for 30 minutes. 4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline (149 mg, 0.45 mmol) from Example 15A was added to the suspension and the mixture heated to 50° C. overnight. After cooling to room temperature the mixture was concentrated under reduced pressure and the residue purified by silica gel chromatography (ethyl acetate/dichloromethane 1:1) to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea (218 mg, 50%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.00 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.52-7.27 (m, 5H), 6.49 (s, 1H), 4.32 (bs, 2H), 4.00 (s, 3H), 3.77 (bs, 2H), 3.36 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 524 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=[C:4]([C:18]2[S:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=2)[N:3]=1.[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[H-].[Na+]>CN(C=O)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:6]2[CH:7]=[C:2]([O:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:3]=[C:4]([C:18]3[S:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=3)[N:5]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(COc2cc(Cl)nc(-c3nc(C(F)(F)F)cs3)n2)cc1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(Oc3ccccc3)nc(-c3nc(C(F)(F)F)cs3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a stirred solution of compound 285 (246 mg, 1 eq.) in anhydrous DMF (5 mL) was added a solution of phenol (69 mg, 1.2 eq.) and NaH 60% in oil (29 mg, 1.2 eq.) in anhydrous DMF (5 mL). The resulting mixture was stirred at room temperature for 3 hrs and concentrated under reduced pressure. The crude material was solubilized in EtOAc (10 mL), and washed sequentially with water and brine. Organics were dried over MgSO4, filtered, and concentrated under reduced pressure to yield compound AH as a beige solid in 100% yield. 1H NMR (CDCl3, 400 MHz) δ 3.82 (s, 3H), 5.48 (s, 2H), 6.01 (s, 1H), 6.83-6.93 (m, 1H), 7.16-7.31 (m; 4H), 4.43 (m, 4H), 7.90 (s, 1H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[N:5]=1)=[N+:2]=[N-:3].C(OC=[C:15]([C:21](=O)[C:22]([F:25])([F:24])[F:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>C(#N)C>[Cl:10][C:6]1[N:5]=[C:4]([N:1]2[C:21]([C:22]([F:23])([F:25])[F:24])=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=[N:2]2)[CH:9]=[CH:8][CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Reactant: [N-]=[N+]=Nc1cccc(Cl)n1
Solvent: CC#N
Product: CCOC(=O)c1nnn(-c2cccc(Cl)n2)c1C(F)(F)F
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of the title compound from Example 330 Step A (300 mg, 1.94 mmol) in acetonitrile (4 mL) was added ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (0.284 mL, 1.94 mmol) followed by TEA (0.271 mL, 1.94 mmol), and the mixture was heated at 70° C. After 16 h, the reaction mixture was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 65% EtOAc in hexanes) provided the title compound as a yellow oil: LCMS m/z 320.85 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 8.03 (t, J=7.9 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 4.55 (q, J=7.2 Hz, 2H), 1.49 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][N:11]2C(=O)C)=[CH:2]1.Cl>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][NH:11]2)=[CH:2]1
Reactant: CC(=O)N1CCc2ccccc2C1c1c[nH]c2ccccc12
Agent: Cl
Solvent: CO
Product: c1ccc2c(c1)CCNC2c1c[nH]c2ccccc12
Temperature: 100 °C

Procedure:
To a solution 1-(1-(1H-indol-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (50 mg, 172 μmol in MeOH (1.0 mL) was added 5 M HCl (1.0 mL, 5000 μmol). The reaction was heated to 100° C. under microwave 30 min. The reaction was concentrated to give 1-(1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline, which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[C:4]([CH3:14])[CH:3]=1.C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>>[F:1][C:2]1[CH:13]=[C:12]2[C:5](=[C:4]([CH3:14])[CH:3]=1)[N:6]([CH2:7][C:8]([F:9])([F:10])[F:11])[CH:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]2=[O:17]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1cc(F)ccc1NCC(F)(F)F
Product: CCOC(=O)c1cn(CC(F)(F)F)c2c(C)cc(F)cc2c1=O
Temperature: 0 °C
Yield: 42.8 %

Procedure:
A mixture of 66.1 g of 4-fluoro-2-methyl-N-(2,2,2-trifluoroethyl)aniline and 75.0 g of diethyl ethoxymethylenemalonate was heated at 160° for 20 hours. Eight hundred grams of polyphosphoric acid (ca. 400 ml) was added and the resulting mixture heated at 105°-115° for 20 minutes. The hot reaction mass was poured onto 1 kg of cracked ice to hydrolyze the polyphosphoric acid; the resulting solid was filtered and recrystallized from acetonitrile to yield 45.2 g of 6-fluoro-1,4-dihydro-8-methyl-4-oxo-1-(2,2,2-trifluoroethyl)-3-quinolinecarboxylic acid, ethyl ester, m.p. 154°-158°.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[N:8][C:9]3[CH2:15][CH2:14][CH2:13][C:10]=3[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[Cu].C1(C)C(C)=CC=CC=1>[C:19]1([CH2:18][O:1][C:2]2[C:7]3=[N:8][C:9]4[CH2:15][CH2:14][CH2:13][C:10]=4[C:11](=[O:12])[N:6]3[CH:5]=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c2c(nc3c(O)cccn13)CCC2
Agent: [Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: O=c1c2c(nc3c(OCc4ccccc4)cccn13)CCC2

Procedure:
A stirred mixture of 6.1 g. of 2,3-dihydro-5-hydroxycyclopenta[d]pyrido[1,2-a]pyrimidin-10(1H)-one, 1.40 g. of powdered sodium hydroxide, 100 ml of xylene, 100 mg of copper bronze, and 6.2 g. of benzyl bromide are stirred and heated under reflux for 12 hours, and filtered hot. From the filtrate, on cooling, the product crystallizes. It is filtered and recrystallized from xylene to give 6.3 g. of product, m.p. 150°-152°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[N:11]#[C:12][NH2:13].[N+:14]([O-:17])([OH:16])=[O:15].NC(N)=N>>[N+:14]([O-:17])([OH:16])=[O:15].[NH:1]([C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1)[C:12]([NH2:13])=[NH:11]
Reactant: Nc1ccc2ncsc2c1
Reactant: N#CN
Agent: N=C(N)N
Solvent: O=[N+]([O-])O
Product: N=C(N)Nc1ccc2ncsc2c1

Procedure:
6-Guanidinobenzothiazole nitrate was prepared from 6-aminobenzothiazole (1.50 g, 10.0 mmol), cyanamide (630 mg in 1.26 ml H2O, 15.0 mmol) and concentrated nitric acid (1 ml) following the method described for the guanidine of Example 1 to give the compound as a peach solid (1.27 g) m.p. 202-204°. MS (ES+) 192 (MH+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: COC(=O)c1nc(Br)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 45.7 %

Procedure:
A mixture of 1,3-dibenzyl-8-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (105 mg, 0.22 mmol), 3-tributylstannanyl-pyridine (0.1 mL, 0.33 mmol) and PdCl2(PPh3)2 (30 mg, 0.044 mmol) in 5 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc (50 mL) and brine (10 mL) were added. 1M HCl was added with stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-80% EtOAc/hexanes+2% AcOH) to give 48 mg of the title compound. MS: (+) m/z 478.16 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][CH2:15][OH:16])=[CH:8][CH:7]=1)=[CH2:5])C.[Br:25]N1C(=O)CCC1=O>O1CCCC1.O>[Br:25][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][CH2:15][OH:16])=[CH:8][CH:7]=1)=[O:5]
Reactant: C=C(OCC)c1ccc(C[C@@H](CCO)NC(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCO)Cc1ccc(C(=O)CBr)cc1
Yield: 100 %

Procedure:
To a cooled (0° C.) solution of 1,1-dimethylethyl [(1S)-1-({4-[1-(ethyloxy)ethenyl]phenyl}methyl)-3-hydroxypropyl]carbamate (15 g, 44 mmol) in tetrahydrofuran (450 mL) and water (150 mL) was added N-bromosuccinimide. The resulting solution was allowed to warn to room temperature and maintained for 90 minutes. The reaction was then concentrated and diluted with ethyl acetate (1 L). The resulting solution was washed with water (1 L) and brine (500 mL), dried (MgSO4) and concentrated to give 19.5 g (˜100%) of 1,1-dimethylethyl ((1S)-1-{[4-(bromoacetyl)phenyl]methyl}-3-hydroxypropyl)carbamate as a slightly yellow solid. ESMS [M+H]+: 386.2.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:15]([OH:18])[CH2:16]Cl)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C.ClCCl>[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:15]1[O:18][CH2:16]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
A solution of potassium hydroxide (6.52 g. 0.116 mol, 1.2 equiv.) in 970 mL of absolute ethanol was treated with N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol (32.3 g, 0.097 mol). This solution was stirred at room temperature for 15 minutes and then concentrated in vacuo to give a white solid. The solid was dissovled -20 in dichloromethane and washed with water, dried over anhyd MgSO4, filetered and concentrated in vacuo to give a white solid. The solid was crystallized from hexanes and ethyl acetate to give 22.3 g, 77% of 3(S)-(N-(benzyloxycarbonyl)amino]-1,2(S)-epoxy-4-phenylbutane, mp 102-103° C., FAB MS: MH+ =298.
Reaction SMILES: S([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]1[CH2:30][C:29]2[CH:28]=[C:27]([OH:31])[CH:26]=[CH:25][C:24]=2[C@@H:23]2[C@@H:14]1[C@H:15]1[C@@:19]([CH2:21][CH2:22]2)([CH3:20])[C@@H:18]([OH:32])[CH2:17][CH2:16]1)(C)(=O)=O.[Br-].C[Si](C)(C(C)(C)C)OCCCCCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:67]([S:72][CH2:73][CH2:74]O)[CH2:68][CH2:69][CH2:70][CH3:71]>>[CH2:67]([S:72][CH2:73][CH2:74][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]1[CH2:30][C:29]2[CH:28]=[C:27]([OH:31])[CH:26]=[CH:25][C:24]=2[C@@H:23]2[C@@H:14]1[C@H:15]1[C@@:19]([CH2:21][CH2:22]2)([CH3:20])[C@@H:18]([OH:32])[CH2:17][CH2:16]1)[CH2:68][CH2:69][CH2:70][CH3:71]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCOS(C)(=O)=O)[C@H]3[C@@H]1CC[C@@H]2O
Reactant: CCCCCSCCO
Agent: CC(C)(C)[Si](C)(C)OCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCCCSCCOCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12

Procedure:
The process described in Example 32 was repeated using 7α-(7-mesyloxyheptyl)oestra-1,3,5(10)-triene-3,17β-diol (obtained as described in Example 41 using initially 6-(dimethyl-t-butylsilyloxy)hexyltriphenylphosphonium bromide) and 2-n-pentylthio-ethanol (obtained from pentanethiol and 2-bromoethanol) as starting materials. There was thus obtained as an oil 7α-[7-(2-n-pentylthioethoxy)heptyl]oestra-1,3,5(10)-triene-3,17β-diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Mg].C(Br)CBr.[C:19]([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[C:4]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]=[CH:6][CH:1]=[CH:2][C:3]=1[C:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)[OH:26]
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: O=C(c1ccccc1)c1ccncc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: OC(c1ccccc1)(c1ccncc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 111.0 g (0.50 mole) of 4-biphenyl bromide in 200 ml of dry tetrahydrofuran (THF) was added slowly to a mixture of 12.10 g (0.5 gram-atom) of magnesium, 2 ml of ethylenedibromide and 200 ml of THF at such a rate as to maintain reflux. After addition the mixture was refluxed for 0.5 hours, cooled and treated over 0.5 hours with a solution of 82.3 g (0.45 mole) of 4-benzoylpyridine in 600 ml THF. The resulting slurry was stirred 0.5 hours at 25° C. and treated with 1000 ml 20% ammonium chloride solution. The organic layer was separated, filtered, the filtrate dried, filtered and stripped. The residue was triturated with ether and filtered. This solid was recrystallized from ethanol, chloroform, and finally toluene to give α-(1,4'-biphenyl)-yl-α-phenyl-4-pyridinemethanol as a white solid, m.p. after drying in vacuo at 70° C.; 173.5°-175.5° C.
Reaction SMILES: C([S:8][C:9]1([CH2:15][N:16]([CH2:18][CH2:19][P:20]([CH3:23])([CH3:22])=S)[CH3:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)C1C=CC=CC=1.[Na].[Cl-].[NH4+]>O1CCCC1.C(Cl)(Cl)Cl>[SH:8][C:9]1([CH2:15][N:16]([CH2:18][CH2:19][P:20]([CH3:23])[CH3:22])[CH3:17])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: CN(CCP(C)(C)=S)CC1(SCc2ccccc2)CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN(CCP(C)C)CC1(S)CCOCC1
Temperature: -50 °C

Procedure:
A solution of 4-benzylthio-4-[N-(2-dimethylphosphinothioylethyl)-N-(methyl)aminomethyl]-2,3,5,6-tetrahydro-4H-pyran (500 mg) in dry tetrahydrofuran (10 cm3) was placed in a flask fitted with a low temperature condenser (-50° C.), drying tube and gas inlet. The flask was flushed with nitrogen, the solution cooled to -50° C., and then dry ammonia (40 cm3) was condensed into the flask. Small pieces of sodium were then added to this mixture until the blue colouration persisted for at least 1 hour. The blue colouration was then discharged by the addition of ammonium chloride, and the mixture allowed to warm to room temperature. As the ammonia evaporated steps were taken to ensure that no air entered the apparatus. [The flask and its contents were then transfered to a glove box containing a nitrogen atmosphere for subsequent operations.] The reaction mixture was filtered and the solvent removed under reduced pressure to give a yellow oil containing some solid material. The oil was dissolved in chloroform, the solid removed by filtration, and the solvent removed under reduced pressure to give the phosphine as a colourless oil.