Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:38]1[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:34])[CH3:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:38]4[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reactant: Cc1ccc(Cl)nn1
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccc(F)cc4)OC3=O)cc2)nn1

Procedure:
The title compound was prepared from (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 3-chloro-6-methylpyridazine following a procedure analogous to that described in Example 459 Step 4. LC-MS Method 2 tR=1.163 min, m/z=464; 1H NMR (CDCl3) 1.12 (d, 6H), 1.55 (d, 3H), 2.18 (s, 2H), 2.19-2.28 (m, 2H), 2.40 (m, 1H), 2.74 (s, 3H), 2.90 (m, 1H), 5.71 (m, 1H), 6.96-7.05 (t, 2H), 7.10 (d, 2H), 7.29 (m, 2H), 7.38 (d, 2H), 7.69 (d, 1H), 7.82 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[N:7]=[C:6]([C:12]2[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([O:17][CH3:18])[C:11]=2[O:10][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(B(O)O)c(OC)c1OC
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccnc(Cl)n2)c(OC)c1OC
Yield: 74.1 %

Procedure:
In a 250 mL round-bottomed flask, 1.49 grams (10 mmol) of 2,4-dichloropyrimidine was combined with 2,3,4-trimethoxyphenylboronic acid (2.12 g, 10 mmol), sodium carbonate (2.12 g, 2 equivalents), and 1.15 g (0.1 equivalents) of tetrakis-triphenylphosphinepalladium. Toluene (50 mL) and water (5 mL) were added. The reaction was allowed to reflux under nitrogen overnight. The reaction was diluted with toluene and water and the organic layer was separated, washed with brine, dried (Na2SO4), filtered, and concentrated to afford the crude pyrimidine 5. The compound was purified on silica gel using an eluent of 30% acetone/hexane to afford 2.08 g (74%) of the product 5 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7]O)=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:4][N:3]=1.CS([Cl:19])(=O)=O>ClCCl>[Cl:1][C:2]1[C:6]([CH2:7][Cl:19])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: OCc1c(Cl)nsc1-c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: ClCc1c(Cl)nsc1-c1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Into a 25-mL round-bottom flask, was placed (3-chloro-5-phenyl-1,2-thiazol-4-yl)methanol (80 mg, 0.34 mmol, 1.00 equiv, 97%), MsCl (81.6 mg, 0.72 mmol, 2.00 equiv), TEA (107.7 mg, 1.06 mmol, 3.00 equiv), dichloromethane (1.5 mL). The resulting solution was stirred for 1 h at 20° C. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3×5 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 85 mg (96%) of 3-chloro-4-(chloromethyl)-5-phenyl-1,2-thiazole as yellow oil.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=O.O1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[CH:12]1([N:8]=[C:1]=[N:3][CH:7]2[CH2:6][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:11][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
Malonitrile is alkylated (or dialkylated) by treatment with NaH in an appropriate solvent such as dimethylformamide or tetrahydrofuran at 0° to 25° C. to give compounds (51). Treatment of the substituted nitrile with (n-Bu)3SnN3 in refluxing dioxane for 24 hours gives, after acidic hydrolysis, the tetrazole (52), which is then alkylated with an alkyl halide (R4Br) in CH3CN employing Et3N as base to give a mixture of regioisomers (53) and (54). The regioisomers are then separated by flash chromatography and each nitrile is then reduced to the corresponding aldehydes (55) and (56) by treatment with Raney nickel in formic acid at 60° C. The resulting aldehydes are then treated with a stabilized ylide such as ethyl(triphenylphosphoranylidene)acetate in CH2Cl2 at room temperature to give (57) and (58) which are reduced catalytically using hydrogen gas, Pd/C as catalyst in methanol or ethanol at room temperature to give esters (59) and (60). These are then hydrolyzed to the corresponding acids (61) and (62) by treatment with alcoholic (MeOH/EtOH) alkali metal hydroxide (NaOH or KOH) at reflux. The acids are then coupled with an appropriate amine employing carbonyldiimidazole in tetrahydrofuran at room temperature or dicyclohexylcarbodiimide in CH2Cl2 at 0° C. to give amides (63) and (64).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(C(C)C)CC)(C)C.[N:23]1[NH:24][N:25]=[N:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:52]=[CH:51][C:37]2[N:38]([CH:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:42](O)=[O:43])[CH:39]=[N:40][C:36]=2[CH:35]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>>[O:43]=[C:42]([NH:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:41]([N:38]1[C:37]2[CH:51]=[CH:52][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[C:27]3[N:23]=[N:24][NH:25][N:26]=3)=[CH:35][C:36]=2[N:40]=[CH:39]1)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCC(C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCC(C(=O)N[C@@H](Cc1ccccc1)C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21

Procedure:
L-Phenylalanine hydrochloride (1.75 mmoles, 380 mg), diisopropylethylamine (1.93 mmoles, 0.34 ml), 2-[5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazol-1-yl]octanoic acid (1.24 mmoles, 0.50 g), hydroxybenzotriazole (1.36 mmoles 184 mg) and dicyclohexylcarbodiimide (1.36 mmoles, 280 mg) were reacted as in Example 37. The stereoisomers were separated by chromatography over silica gel eluted with 2% methanol in chloroform. The isomers were hydrolyzed as in Example 37 to yield N-[1-oxo-2-[5-[2-(2H-tetrazole-5-yl]phenyl]-1H-benz imidazol-1-yl]octyl]-L-phenylalanine.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[NH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1.CN(C=O)C>O>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: c1ccc2c(c1)CCCN2
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCCc2ccccc21)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (100 mg, 0.46 mmol), 1,2,3,4-tetrahydroquinoline (122 mg, 0.92 mmol) and DMF (1 ml) was stirred at 80° C. for 8 hours. The reaction mixture was allowed to return to room temperature. To the solution, water was added, and the resulting solution was extracted with ethyl acetate twice. The organic phases were combined, washed with water twice and a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-3-(3,4-dihydro-2H-quinolin-1-yl)-2-methylpropan-2-ol (134 mg, yield 83%) as an orange oil.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:7]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:32])C=CC=CC=1>C(Cl)(Cl)Cl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:32])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:7]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CCOCCOc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Solvent: ClC(Cl)Cl
Product: CCOCCOc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of 8-cyclopentyl-6-(2-ethoxy-ethoxy)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (289 mg, 0.83 mmol) in chloroform (5 mL) was added 2-benzenesulfonyl-3-phenyl-oxaziridine (281 mg, 1.07 mmol). The reaction mixture was stirred at RT overnight, under nitrogen. The solvents were removed and the crude product was chromatographed on silica gel, eluting with a 5% methanol-ethyl acetate/hexane gradient to give 8-cyclopentyl-6-(2-ethoxy-ethoxy)-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one as a clear oil (210 mg, 0.56 mmol). 1H NMR δ(400 MHz, CDCl3) 8.84 (s, 1H), 6.89 (s, 1H), 6.06-5.98 (m, 1H), 4.23 (t, J=4.0 Hz, 2H), 3.89 (t, J=4.0 Hz, 2H), 3.60 (q, J=6.9 Hz, 2H), 2.95 (s, 3H), 2.28-2.19 (m, 2H), 2.15-2.10 (m, 2H), 1.97-1.88 (m, 2H), 1.71-1.64 (m, 2H), 1.21 (t, J=6.9 Hz, 3H); MS (APCI+) 350 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[CH:13][N:14]=[C:7]1[CH:6]=[CH:5]2.[CH2:15]([CH:17]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:18][O:19][C:20](=[O:24])[CH2:21][CH2:22][SH:23])[CH3:16].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.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]>[CH2:15]([CH:17]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:18][O:19][C:20](=[O:24])[CH2:21][CH2:22][S:23][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[CH:13][N:14]=[C:7]1[CH:6]=[CH:5]2)[CH3:16]
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: Brc1ccc2c(ccc3ncnn32)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCCCC(CC)COC(=O)CCSc1ccc2c(ccc3ncnn32)c1
Temperature: 110 °C

Procedure:
8b (120 mg, 0.48 mmol) and 3-mercaptopropionic acid 2-ethylhexyl ester (110 mg, 0.55 mmol) were dissolved in 1,4-dioxane (5 mL) and degassed for 10 minutes with N2. iPr2NEt (0.16 mL, 0.89 mmol) was added, followed by Pd2dba3 (10 mg, 0.01 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12 mg, 0.02 mmol), and the mixture was degassed with N2 for an additional 10 minutes. The reaction was sealed and heated at 110° C. for 4 hours. The reaction was cooled to room temperature and purified by silica gel chromatography (25-100% EtOAc in hexanes) to give the desired product, 8e.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:22]([N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1)[CH2:23][CH2:24][CH3:25]
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1CCC2(C=Cc3ccccc32)CC1
Yield: 31.3 %

Procedure:
In the same way as that described in Example 1, step 5, the title compound was prepared, using spiro[1H-indene-1,4'-piperidine] (333 mg, 1.8 mmol), DMF (15 ml), potassium carbonate (0.26 g, 1.9 mmol) and iodobutane (267 μl, 2.4 mmol). The crude residue was chromatographed in dichloromethane:methanol 95:5, to give 1'-butylspiro [1H-indene-1,4'-piperidine] (136 mg, 31%) as a clear oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:25][CH2:24]2)=[O:22])[CH:38]=[CH:37][CH:36]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)C(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Product: CC(C)C(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2-c2cccc(Cl)c2)CC1
Yield: 47 %

Procedure:
The title compound was synthesized in analogy to example 5, from 1-{4-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carbonyl]-piperazin-1-yl}-2-methyl-propan-1-one (example 31) and 3-chlorophenylboronic acid to afford the desired product as a light-brown foam (47%). MS (ISP): 564.5 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[S:11][N:10]=[C:9]([CH:12](Br)[C:13]([O:15][CH3:16])=[O:14])[N:8]=1)=[O:5])[CH3:2].C(#N)C.[N+]1([O-:27])C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4]([NH:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[O:27])[C:13]([O:15][CH3:16])=[O:14])[N:8]=1)=[O:5])[CH3:2]
Reactant: [O-][n+]1ccccc1
Reactant: CCOC(=O)Nc1nc(C(Br)C(=O)OC)ns1
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)Nc1nc(C(=O)C(=O)OC)ns1
Yield: 93.6 %

Procedure:
Into a 1 L round bottom flask equipped with mechanical stirring and reflux condenser was charged methyl 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)-bromoacetate (50.0 g, 0.154 mol, 1.0 eq.) followed by acetonitrile (500 mL). To the clear light yellow solution was charged pyridine N-oxide (37.0 g, 0.385 mol, 2.5 eq) and the reaction mixture was heated to reflux and maintained there for three hours until reaction completion was determined by proton NMR analysis. The solution was cooled and the acetonitrile was removed by rotary evaporation to give a thin yellow oil. The oil was dissolved in dichloromethane (500 mL) and the organic was washed once with brine (1×200 mL). The brine solution was extracted several times with dichloromethane (5×100 mL) and the organic layers were combined and dried with sodium sulfate, filtered and the solvent evaporated to give a clear slightly yellow oil which solidified upon standing at room temperature. The solid was dried under high vacuum to give 37.36 grams of the title compound. 1H NMR (CDCl3) δ 1.40 (t, 3H); 4.06 (s, 3H); 4.46 (q, 2H).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH:8]([S:14](Cl)(=[O:16])=[O:15])([S:10](Cl)(=[O:12])=[O:11])[CH3:9].C(S(Cl)(=O)=O)S(Cl)(=O)=O.C(N(CC)CC)C.C(O)(O)CCCC.C(S(Cl)(=O)=O)CS(Cl)(=O)=O>C(COC)OC>[CH:8]1([S:14](=[O:16])(=[O:15])[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][S:10]1(=[O:12])=[O:11])[CH3:9]
Reactant: CC(S(=O)(=O)Cl)S(=O)(=O)Cl
Reactant: OCCCCCO
Agent: CCCCC(O)O
Agent: O=S(=O)(Cl)CCS(=O)(=O)Cl
Agent: O=S(=O)(Cl)CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CC1S(=O)(=O)OCCCCCOS1(=O)=O
Reaction time: 0.75 h

Procedure:
1,5-Pentanediol (4.17 g, 0.04 mole) was dissolved in 350 ml of glyme in a 1 liter round bottom flask and the solution brought to -20° C. 1,1-ethanedisulfonyl chloride, synthesized in the same manner as the methanedisulfonyl chloride, (Example I) was dissolved in 25 ml of glyme and this solution added dropwise to the solution in the flask. Triethylamine (8.08 g, 0.08 mole) was dissolved in 125 ml of glyme and this solution was added to the pentanediol/ ethanedisulfonyl chloride solution over a 1 hour period. After the additions were completed, the mixture was brought to 25° C. over a 45 minute period in a water bath. The mixture was roto-evaporated under reduced pressure, at a temperature below 35° C. The residue was washed three times with 20 ml of 5% sodium bicarbonate the resulting emulsion being separated by centrifugation. Water was decanted from the final oil wash, and methylene chloride was added. This solvent apparently dissolved all or most of the impurities, leaving the product suspended in the solution. The product was obtained by vacuum filtering the solution through Whatman #5 qualitative filter papers.
Reaction SMILES: O1CCC(=O)CC1.[C:8]([O:12][C:13]([N:15]1CCC(=O)CC1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[NH2:22][C:23]1([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:28][CH2:27]O[CH2:25][CH2:24]1>>[NH2:22][C:23]1([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:28][CH2:27][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:25][CH2:24]1
Reactant: COC(=O)CC1(N)CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=C1CCOCC1
Product: COC(=O)CC1(N)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Instead of tetrahydro-4H-pyran-4-one, 1-(tert-butoxycarbonyl)-4-piperidone (5.00 g) was used and treated by the same techniques as in Reference Example 1-1(1) and (2) to give the titled compound as a colorless solid (4.65 g).
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)[CH2:8][CH2:9][CH3:10])[CH3:7]
Reactant: CCCC(Br)C(=O)OCC
Reactant: COc1ccc(S)cc1
Product: CCCC(Sc1ccc(OC)cc1)C(=O)OCC

Procedure:
2-(4-Methoxy-phenylsulfanyl)-pentanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromovalerate (8.23 g, 39.3 mmol) and 4-methoxythiophenol (5 g, 35.7 mmol), 10.46 g (100%); clear oil; MS: 269 (M+H)+.
Reaction SMILES: ClC(Cl)=C[C@H]1[C@H](C(Cl)=O)C1(C)C.[Cl:13][C:14]([Cl:40])=[CH:15][C@H:16]1[C@H:18]([C:19]([O:21][CH2:22][C:23]2[C:28]3[CH2:29][CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:27]=3[CH:26]=[CH:25][CH:24]=2)=[O:20])[C:17]1([CH3:39])[CH3:38]>>[Cl:13][C:14]([Cl:40])=[CH:15][CH:16]1[CH:18]([C:19]([O:21][CH2:22][C:23]2[C:28]3[CH2:29][CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:27]=3[CH:26]=[CH:25][CH:24]=2)=[O:20])[C:17]1([CH3:38])[CH3:39]
Reactant: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1cccc2c1CCCc1ccccc1-2
Agent: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OCc1cccc2c1CCCc1ccccc1-2

Procedure:
Similarly, but employing trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride, (6,7-dihydro-5H-dibenzo[a,c]-cyclohepten-4-yl)methyl trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate was prepared.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[NH2:26]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[C:3]3[N:10]([CH2:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: COC(=O)c1cccc(Cn2ccc3ncnc(Cl)c32)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 89.6 %

Procedure:
To a solution of methyl 3-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoate (670 mg) in 1-methyl-2-pyrrolidone (3.0 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (549 mg), and the reaction mixture was stirred at 120° C. for 1.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (50 mL), and extracted with ethyl acetate (50 mL×3). The organic layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:hexane/ethyl acetate=9/1→0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (1010 mg) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([N:19]1[C:23](=O)[CH:22]([CH2:25][O:26][CH3:27])[O:21][CH-]1)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[K+]>O>[CH3:27][O:26][CH2:25][CH:22]([OH:21])[CH2:23][NH:19][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH:15]=1
Reactant: COCC1O[CH-]N(c2ccc3cc(OCc4ccccc4)ccc3c2)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCC(O)CNc1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A mixture of 2.0 g of 3-(6-benzyloxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone, 20 ml of ethanol, 4 ml of water and 1.08 g of potassium hydroxide is stirred at 100° C. for one hour. The reaction mixture is evaporated under reduced pressure to remove the ethanol. The residue is extracted with ethyl acetate, and the extract is washed with water, dried and evaporated under reduced pressure to remove the solvent. The residue is recrystallized from ethyl acetate-hexane to give 1.64 g of N-(3-methoxy-2-hydroxypropyl)-6-benzyloxy-2-naphthylamine as colorless needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[OH:9].[OH-:10].[K+].Cl>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:10])[C:3]=1[OH:9]
Reactant: Oc1c(F)cccc1I
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: Oc1cccc(F)c1O
Reaction time: 8 h
Yield: 78 %

Procedure:
To a 500 ml flask were added 119 g (0.5 mol) of 2-fluoro-6-iodophenol and 200 ml of a 30% aqueous potassium hydroxide solution and they were reacted under vigorous stirring under a reflux temperature for 8 hours. After the termination of the reaction, the mixture was cooled to ordinary temperature and neutralized with hydrochloric acid to adjust pH between 2 and 3. After filtration, the filtrate was washed with water to obtain 49.9 g of a product [H]. The process yield was 78%.
Reaction SMILES: [CH3:1][CH:2]([C:10]1[CH:11]=[C:12]([OH:26])[C:13]2[CH:14]([CH3:25])[C:15]3[CH2:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]=3[O:21][C:22]=2[CH:23]=1)[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC1C=CC(C(C)C)=CC=1>[Pd].C(Cl)(Cl)Cl>[CH3:1][CH:2]([C:10]1[CH:11]=[C:12]([OH:26])[C:13]2[CH:14]([CH3:25])[C:15]3[C:20]([O:21][C:22]=2[CH:23]=1)=[CH:19][C:18]([CH3:24])=[CH:17][CH:16]=3)[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC1=C(CCC(C)C1)C2C
Agent: [Pd]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)Oc1cc(C)ccc1C2C

Procedure:
A solution of 1.7 g. of 3-(1,2-dimethylheptyl)-5,6,7,8-tetrahydro-1-hydroxy-6,9-dimethylxanthene in 70 ml. of p-cymene is added dropwise over one hour to a stirred suspension of 0.56 g. of 10% palladium-on-carbon in 70 ml. of refluxing p-cymene under a nitrogen atmosphere. The reaction mixture is refluxed for four hours, cooled and chloroform is added. The mixture is filtered and the filtrate is concentrated in vacuo to give a residue which is chromatographed on silica gel with 1:1 chloroform-cyclohexane as eluant to give the title compound, b.p. 208°-210° (0.004 mm.).