Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[CH3:15][C:16]1[C:22](=[O:23])[NH:21][C:19](=[O:20])[N:18]([C@@H:24]2[O:28][C@H:27]([CH2:29][OH:30])[C@@H:26]([N:31]=[N+:32]=[N-:33])[CH2:25]2)[CH:17]=1.C[O-].[Na+].C(Cl)(Cl)Cl.CO.CC(O)=O>CN1C(=O)N(C)CCC1>[C:8]1(=[O:9])[N:4]([CH2:3][CH2:2][N:21]2[C:22](=[O:23])[C:16]([CH3:15])=[CH:17][N:18]([C@@H:24]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:26]([N:31]=[N+:32]=[N-:33])[CH2:25]3)[C:19]2=[O:20])[C:5](=[O:14])[C:6]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:7]12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 70 °C

Procedure:
A solution of 300 mg N-(2-bromoethyl)-phthalimide (BEP) and 274 mg AZT in 1 ml of sieve-dried DMPU was treated with 300 ul of sodium methoxide solution (4.4M NaOMe in MeOH) and heated at 70° C. for one hour. Another 300 ul of NaOMe solution and 175 mg BEP were added and the solution again heated at 70° C. for a total of 3.5 hours. The reaction was followed by analytical TLC on silica gel-F 250 um using a solvent system of CHCl3 /MeOH/HOAc (95+5+0.5) and was found to be incomplete. Addition of more NaOMe solution and BEP did not increase the yield of the desired product. Unreacted BEP (Rf =0.81) and AZT (Rf =0.2) were identified using reference markers and by their UV spectra. The product (Rf =0.4) and a byproduct (Rf =0.62) were differentiated on the basis of their UV spectra and immunological activity. The reaction mixture was acidified with HOAc, diluted with 15 ml deionized water and extracted with EtOAc. The organic phase was washed with saturated NaCl solution, dried over Na2SO4, concentrated under reduced pressure and chromatographed by preparative TLC on silica gel-F 2000 um using the solvent system CHCl3 /MeOH/HOAc (96.5+3.3+0.3) and the product eluted with MeOH.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](O)=[O:9])[S:5][C:6]=1[Cl:7].S(Cl)(Cl)=O.[BH4-].[Na+].O>C(Cl)Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[S:5][C:6]=1[Cl:7]
Reactant: O=C(O)c1cc(Cl)c(Cl)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: OCc1cc(Cl)c(Cl)s1
Temperature: 0 °C
Yield: 144.9 %

Procedure:
To a solution of 4,5-Dichloro-thiophene-2-carboxylic acid (0.500 grams, 2.53 mmole) and thionyl chloride (1.0 ml) in methylene chloride (10 ml) was refluxed for 3 hours. The mixture was concentrated to remove solvent and diluted with 15 ml dioxane and sodium borohydride (0.143 grams, 3.8 mmole) and refluxed for 3 hours. The mixture was cooled to 0° C. and 3 ml water was added dropwise. The mixture was poured into 100 ml water. This was extracted with diethyl ether, washed with 1N NaOH, water, and brine, dried over MgSO4, filtered and concentrated to an oil which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent to give an oil (0.671 g). MW 183.06; MS (m/e) 184 (M++1).
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[C:11]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(=[O:13])[CH3:12]>O1CCCC1>[CH2:8]([O:7][C:3](=[O:10])[CH2:12][C:11](=[O:13])[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH3:9]
Reactant: CC(=O)c1cccs1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cccs1
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A 0.254 g portion of 60% sodium hydride and 1.95 g of diethyl carbonate were charged using 1.0 ml of tetrahydrofuran at 24° C. and then the temperature was increased to carry out reflux. At said temperature (79° C.) a solution prepared by dissolving 0.5 g of 2-acetylthiophene in 1 ml of tetrahydrofuran was added dropwise thereto spending 15 minutes. Thereafter, the mixture was stirred at said temperature for 1 hour, and when the reaction was completed, the reaction solution was analyzed by a liquid chromatography under the same conditions of the aforementioned Production Example 1 to find that the reaction yield was 89%.
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=1[CH3:25])[CH:12]=2)[C:3]([O:5]C)=O.[NH2:32][C:33]([NH2:35])=[S:34].C([O-])(=O)C.[Na+]>C(O)C>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:21][C:20]=1[CH2:19][O:18][C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:8]([CH2:7][CH:2]3[S:34][C:33](=[NH:32])[NH:35][C:3]3=[O:5])[CH:9]=[N:10]2)=[CH:15][CH:14]=1
Reactant: COC(=O)C(Br)Cc1cnc2cc(OCc3nc(-c4ccccc4)oc3C)ccc2c1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CC3SC(=N)NC3=O)cnc2c1

Procedure:
In ethanol (10 mL) was dissolved the crude residue (300 mg) of methyl 2-bromo-3-[7-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-quinolyl]propionate. The solution was heated under reflux for 5 hours after addition of thiourea (47 mg, 0.62 mmol.) and sodium acetate (51 mg, 0.62 mmol.).
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[OH-].[Na+].[CH2:9]([O:16][C:17](Cl)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]([NH:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 4 °C
Reaction time: 1 h

Procedure:
Nα -Benzyloxycarbonyl-D-alanine is prepared in the following manner. To a solution of 12.5 g. of D-alanine in 70 ml. of 2N sodium hydroxide, with ice cooling and stirring, is added in simultaneous dropwise addition 24 g. of benzyloxycarbonyl chloride and 35 ml. of 4N sodium hydroxide. The pH is maintained at 10 to 12 using a pH electrode in the reaction vessel. The reaction is stirred for one hour further at 4° C. and then extracted with 100 ml. of ethyl ether and acidified to pH 3 with concentrated hydrochloric acid. The product precipitates and is separated by filtration and dried in air; 23.5 g., m.p. 82°-85° C.; [α]D25 + 14.8° (c. 1, 1N acetic acid). A second crop can be obtained from the filtrate by concentration and cooling.
Reaction SMILES: Br[C:2]1[N:6](S(C2C=CC=CC=2)(=O)=O)[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]1([C:3]2[C:4]([C:16]([O:18][CH3:19])=[O:17])=[CH:5][NH:6][C:2]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1cn(S(=O)(=O)c2ccccc2)c(Br)c1-c1ccccc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1c[nH]c(-c2ccccc2)c1-c1ccccc1
Yield: 75.9 %

Procedure:
Using methyl 5-bromo-4-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (1.01 g), phenylboronic acid (439 mg), sodium carbonate (771 mg) and tetrakis(triphenylphosphine)palladium (420 mg), a procedure as in Reference Example 56 was performed to give the title compound as pale-yellow crystals (yield 506 mg, 76%).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][N:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O=S(Cl)Cl.CCN(C(C)C)C(C)C.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[S:45][NH2:46])C=CC=CC=1>C(Cl)Cl>[SH:45][NH:46][C:20](=[O:21])/[CH:19]=[CH:18]/[C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[N:10][O:9][CH2:8][C:7]2[CH:23]=[CH:24][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:13][CH:14]=1
Reactant: NSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)/C=C/c1ccc(C=NOCc2ccc([N+](=O)[O-])cc2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C/c1ccc(C=NOCc2ccc([N+](=O)[O-])cc2)cc1)NS

Procedure:
Compound (2E)-3-{4-[(4-Nitro-benzyloxyimino)-methyl]-phenyl}-N-tritylsulfanyl-acrylamide was obtained (0.050 g, 0.08 mmol, 26% yield) by reaction of intermediate C (2E)-3-[4-({[(4-nitrobenzyl)oxy]imino}-methyl)phenyl]acrylic acid (ST3075, 0.100 g, 0.31 mmol) with SOCl2 (34 μL, 0.46 mmol), DIEA (236 μL, 1.38 mmol) and Triphenylmethanesulfenamide (0.098 g, 0.14 mmol) in anhydrous DCM at room temperature.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:5][CH:4]([C:6](O)=[O:7])[CH2:3]1.C(Cl)(=O)C([Cl:13])=O>ClCCl>[F:1][C:2]1([F:9])[CH2:5][CH:4]([C:6]([Cl:13])=[O:7])[CH2:3]1
Reactant: O=C(O)C1CC(F)(F)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)C1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
3,3-Difluorocyclobutanecarboxylic acid (Parkway Scientific, New York, N.Y., USA) (531 mg, 3.90 mmol) was dissolved in dichloromethane (3.00 mL) and oxalyl chloride (1.02 mL, 11.7 mmol) was added. The solution was stirred at room temperature for 4 h before concentrating in vacuo to provide 3,3-difluorocyclobutanecarbonyl chloride (ca. 50% pure), which was carried on without purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]1[C:15]2[CH:16]=[CH:17][O:18][C:14]=2[CH:13](O)[CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:15]2[CH:16]=[CH:17][O:18][C:14]=2[CH2:13][CH2:12][CH:11]=1
Reactant: OC1CCC(c2cc3ccccc3o2)c2ccoc21
Solvent: Cc1ccccc1
Product: C1=C(c2cc3ccccc3o2)c2ccoc2CC1
Yield: 85.3 %

Procedure:
To a mixture of 19.3 g of 4,5,6,7-tetrahydro-4-(2-benzofuryl)-benzofuran-7-ol in 400 mL of toluene was added 100 mg of p-tolenesulfonic acid monohydrate, and the mixture was placed on a Rotovap, and the solvent was distilled in vacuo (60° C.) until a residue was obtained. The residue was chromatographed on silica (hexane/methylene chloride 1.5:1) to afford 15.3 g (86%) of 6,7-dihydro-4-(2-benzofuryl)-benzofuran, (Formula III: R3 =H; ##STR52## R5 =2-benzofuryl) as an orange oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH3:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:18]([O:21][CH2:22][C:23]1[C:24]([N:32]2[N:41]=[CH:40][C:39]3[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=3)[C:33]2=[O:47])=[N:25][CH:26]=[CH:27][C:28]=1B(O)O)(=[O:20])[CH3:19].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:18]([O:21][CH2:22][C:23]1[C:24]([N:32]2[N:41]=[CH:40][C:39]3[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:44])([CH3:43])[CH3:45])[CH:38]=3)[C:33]2=[O:47])=[N:25][CH:26]=[CH:27][C:28]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH3:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:20])[CH3:19]
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Reactant: CC(=O)OCc1c(B(O)O)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)n(C)n3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 119a (180 mg, 0.50 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridine-4-ylboronic acid 116c (207 mg, 0.50 mmol), Pd(dppf)Cl2 (41 mg, 0.050 mmol), K3PO4 (212 mg, 1.0 mmol), sodium acetate (82 mg, 1.0 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 119b as a white solid (175 mg, 60%). MS-ESI: [M+H]+ 586.4
Reaction SMILES: ClC1C2C(C3C=CC=CC=3F)=NCC(=O)N(C)C=2C=C(Cl)C=1N=C=O.[Cl:26][C:27]1[C:32]2[C:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[F:46])=[N:34][CH2:35][C:36](=[O:39])[N:37]([CH3:38])[C:31]=2[CH:30]=[C:29]([Cl:47])[C:28]=1[NH:48][C:49](=[O:53])[N:50](C)[CH3:51].NC1C(Cl)=CC2N(C)C(=O)CN=C(C3C=CC=CC=3F)C=2C=1Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CN.ClCCCl>[Cl:26][C:27]1[C:32]2[C:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[F:46])=[N:34][CH2:35][C:36](=[O:39])[N:37]([CH3:38])[C:31]=2[CH:30]=[C:29]([Cl:47])[C:28]=1[NH:48][C:49]([NH:50][CH3:51])=[O:53]
Reactant: CN(C)C(=O)Nc1c(Cl)cc2c(c1Cl)C(c1ccccc1F)=NCC(=O)N2C
Agent: CN
Agent: CN1C(=O)CN=C(c2ccccc2F)c2c1cc(Cl)c(N)c2Cl
Agent: CN1C(=O)CN=C(c2ccccc2F)c2c1cc(Cl)c(N=C=O)c2Cl
Solvent: CC#N
Solvent: ClCCCl
Product: CNC(=O)Nc1c(Cl)cc2c(c1Cl)C(c1ccccc1F)=NCC(=O)N2C
Temperature: 25 °C
Reaction time: 66 h

Procedure:
A 1,2-dichloroethane solution of [6,8-dichloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate, prepared in analogy to the procedure described in paragraph (a) of Example 4 from 5 g (14.2 mmol) of 7-amino-6,8-dichloro-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one, is treated with a suspension of 6 g of sodium carbonate in 34 ml of acetonitrile and 2 ml of methylamine. The mixture is stirred at room temperature for 66 hours, concentrated in vacuo and the residue is taken up in 1.5 liter of methylene chloride/ethanol (4:1). The organic phase is washed with saturated sodium chloride solution, dried and evaporated. The residue is chromatographed on 300 g of silica gel using methylene chloride/ethyl acetate (4:1) for the elution, there being obtained 1-[6,8-dichloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-methylurea. After recrystallisation from ether, the product melts at 213°-214° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:12][C:13]([N:15]1[CH2:20][C@H:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]3[O:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:27]=3[CH:37]=2)[C@@H:18]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][O:45][CH2:46][C@@H:47]([CH3:51])[CH2:48][O:49][CH3:50])=[CH:40][CH:39]=2)[C@H:17]([CH2:52][NH2:53])[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>ClCCl>[CH2:5]([O:12][C:13]([N:15]1[CH2:20][C@H:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]3[O:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:27]=3[CH:37]=2)[C@@H:18]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][O:45][CH2:46][C@@H:47]([CH3:51])[CH2:48][O:49][CH3:50])=[CH:40][CH:39]=2)[C@H:17]([CH2:52][NH:53][C:1](=[O:3])[CH3:2])[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CN)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CNC(C)=O)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reaction time: 0.5 h

Procedure:
5.936 mmol of acetyl chloride are added to a solution of 5.396 mmol of (3R,4R,5R)-3-aminomethyl-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy -propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester and 6.475 mmol of triethylamine in 80 ml of dichloromethane under argon at 0° C. After 30 minutes, the reaction mixture is quenched with saturated aqueous sodium bicarbonate solution and extracted with tert-butyl methyl ether (2×). The combined organic layers are washed successively with water and brine, dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rt=4.98 (gradient I).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([CH3:20])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl
Reaction time: 15 h
Yield: 47.6 %

Procedure:
To a suspension of (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A20) (10.0 g, 32.6 mmol), tetrakis(triphenylphosphine)palladium (3.76 g, 3.26 mmol) and potassium carbonate (13.5 g, 97.7 mmol) in dioxane/water (9:1; 100 ml) was added at RT trimethylboroxine (4.53 ml, 32.6 mmol). The reaction mixture was stirred under reflux conditions for 15 h, filtered, evaporated and purified by column chromatography on silica gel (hexane/ethyl acetate 19:1) to yield a light yellow solid (4.45 g, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:14][NH2:15])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])=[O:4].[C:16]([CH2:19][C:20](=O)[CH3:21])(=O)[CH3:17].C(N(CC)CC)C>CO>[N+:11]([C:10]1[CH:9]=[CH:8][C:7]([N:14]2[C:20]([CH3:21])=[CH:19][C:16]([CH3:17])=[N:15]2)=[CH:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4])([O-:13])=[O:12]
Reactant: COC(=O)c1cc(NN)ccc1[N+](=O)[O-]
Reactant: CC(=O)CC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-n2nc(C)cc2C)ccc1[N+](=O)[O-]

Procedure:
A solution of 2.84 g (10 mmol) of 3-methoxycarbonyl-4-nitro-phenylhydrazine, 1.0 g (10 mmol) of acetylacetone and 3.0 ml of triethylamine in 40 ml of methanol is stirred overnight at ambient temperature. Then it is evaporated to dryness, the residue is dissolved in about 50 ml of dichloromethane, the solution is washed with 5% sodium hydrogen carbonate solution, dried and evaporated down again. The crude product thus obtained is purified by column chromatography over silica gel (eluant: dichloromethane).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:25]=[C:24]2[C:11]([CH2:12][C:13]3[C:17]([CH3:18])=[C:16]([CH3:19])[N:15]([CH2:20][C@H:21](O)[CH3:22])[C:14]=32)=[CH:10][CH:9]=1.C(N(CC)CC)C.[N-:33]=[N+:34]=[N-:35].[Na+]>ClCCl.CN(C)C=O.O>[N:33]([C@@H:21]([CH3:22])[CH2:20][N:15]1[C:16]([CH3:19])=[C:17]([CH3:18])[C:13]2[CH2:12][C:11]3[C:24]([C:14]1=2)=[CH:25][C:8]([O:7][CH3:6])=[CH:9][CH:10]=3)=[N+:34]=[N-:35]
Reactant: COc1ccc2c(c1)-c1c(c(C)c(C)n1C[C@@H](C)O)C2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)-c1c(c(C)c(C)n1C[C@H](C)N=[N+]=[N-])C2
Yield: 48 %

Procedure:
0.7 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.22 g of (R)-1-(7-methoxy-2,3-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 2.5 ml of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloro-methane, washed twice with 60 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 60 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The green oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.58 g of sodium azide and the reaction mixture was heated to 80° for 18 hours while stirring. After cooling the solution was poured into 70 ml of water and extracted twice times with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 0.64 g (48%) of (S)-1-(2-azido-propyl)-7-methoxy-2,3-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a light yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[O:20]1[CH2:24][CH2:23][C:22]2[CH:25]=[C:26]([CH2:29][NH2:30])[CH:27]=[CH:28][C:21]1=2>>[O:20]1[CH2:24][CH2:23][C:22]2[CH:25]=[C:26]([CH2:29][NH:30][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][C:12]5[O:15][CH2:16][CH2:17][O:18][C:11]=5[CH:10]=4)[C:5]([F:19])=[CH:4][N:3]=3)[CH:27]=[CH:28][C:21]1=2
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: NCc1ccc2c(c1)CCO2
Product: Fc1cnc(NCc2ccc3c(c2)CCO3)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2,3-dihydrobenzo[b]furan-5-ylmethylamine were reacted to give N2-[2,3-dihydrobenzo[b]furan-5-ylmethyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 21.43 min.; purity: 97.5%; MS (m/e): 395.05 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:17][C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccco1
Temperature: 0 °C
Yield: 85.5 %

Procedure:
37 g of ethyl 3-(4-chlorobenzoylamino)-3-(2-furylcarbonyl)propionate are dissolved in 150 ml of chloroform. 64.9 g of phosphorus oxychloride are added dropwise to the solution at room temperature, and the mixture is refluxed at 60° to 70° C. for 8 hours under stirring. After the reaction is completed, the mixture is poured into ice-water. The aqueous mixture is neutrallized with sodium bicarbonate and then extracted with ethyl acetate. The extract is washed with water, dried, treated with activated charcoal and then evaporated under reduced pressure to remove solvent. The residue is crystallized with diisopropyl ether, and then recrystallized from ethanol. 30 g of ethyl 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]acetate are thereby obtained. Yield: 85.5%
Reaction SMILES: [OH:1][CH:2]([CH2:13][N:14]([CH2:28][CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[CH2:15][CH:16]([OH:27])[CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:34]([O:38]CC)(=O)[CH2:35][OH:36]>C1(C)C=CC=CC=1>[CH2:5]([N:4]([CH2:3][CH:2]([OH:1])[CH2:13][N:14]([CH2:28][CH2:29][S:30]([OH:33])(=[O:31])=[O:32])[CH2:15][CH:16]([OH:27])[CH2:17][N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:35](=[O:36])[CH2:34][OH:38])[C:35](=[O:36])[CH2:34][OH:38])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCNCC(O)CN(CCS(=O)(=O)O)CC(O)CNCCCCCCCC
Reactant: CCOC(=O)CO
Solvent: Cc1ccccc1
Product: CCCCCCCCN(CC(O)CN(CCS(=O)(=O)O)CC(O)CN(CCCCCCCC)C(=O)CO)C(=O)CO
Temperature: 100 °C
Reaction time: 7.5 h
Yield: 86.6 %

Procedure:
A reactor was charged with 10 g (0.02 mole) of 11,15-dihydroxy-13-sulfoethyl-9,13,17-triazapentacosane, 50 ml of toluene and 5.1 ml (0.05 mole) of ethyl glycolate, and the contents were heated to 100° C. and continuously stirred for 7.5 hours while purging ethanol formed with a nitrogen stream. After completion of a reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (on 200 g of silica gel, developing solvent: chloroform/methanol=100/1→20/1), thereby obtaining 10.6 g (isolation yield: 91%) of 3,11-dioctyl-2,12-dioxo-7-sulfoethyl-3,7,11-triaza-1, 5,9,13-tridecanetetraol.