Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:42]([N:44]1[C:52](I)=[C:51]2[C:46]([CH:47]=[CH:48][CH:49]=[CH:50]2)=[N:45]1)[CH3:43]>>[CH2:42]([N:44]1[C:52]([C:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:31][CH2:32][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:34][CH2:35]4)=[CH:26][C:9]=3[N:10]=2)=[C:51]2[C:46]([CH:47]=[CH:48][CH:49]=[CH:50]2)=[N:45]1)[CH3:43]
Reactant: CCn1nc2ccccc2c1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Product: CCn1nc2ccccc2c1-c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1

Procedure:
Following the procedures for 143, 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide and 2-ethyl-3-iodo-2H-indazole were reacted to give 190. LCMS m/z: 549.3 (MH+)
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:31]([N:38]([CH2:59][CH2:60][CH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([N+:69]([O-:71])=[O:70])=[CH:65][CH:64]=1)[CH2:39][CH2:40][C:41]1[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([NH2:50])[CH:48]=2)[NH:43][C:42]=1[C:51]1[CH:56]=[C:55]([CH3:57])[CH:54]=[C:53]([CH3:58])[CH:52]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:38]([CH2:59][CH2:60][CH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([N+:69]([O-:71])=[O:70])=[CH:65][CH:64]=1)[CH2:39][CH2:40][C:41]1[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([NH:50][C:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[O:8])[CH:48]=2)[NH:43][C:42]=1[C:51]1[CH:52]=[C:53]([CH3:58])[CH:54]=[C:55]([CH3:57])[CH:56]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(=O)NCC(=O)O
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2ccc([N+](=O)[O-])cc2)Cc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CC(=O)NCC(=O)Nc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc([N+](=O)[O-])cc3)Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 92.4 %

Procedure:
To a solution of acetylaminoacetic acid (32.2 mg in 6 mL dry methylene chloride) was added 48 mg 1-hydroxybenzotriazole followed by 50 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the mixture stirred at room temperature. After 50 minutes, a solution of 3-(2-{benzyl-[4-(4-nitrophenyl)butyl]amino}ethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-ylamine (120 mg in 2 mL methylene chloride) was added and stirring continued. After 4 hours (total), the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title compound (131 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:19][C:18]2[C@:13](C)([CH2:14][CH2:15][C:16](=[O:20])[CH:17]=2)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][CH2:11]2)([CH3:9])[C:7](=[O:22])[CH2:6][CH2:5]1.O>C(O)(=O)C>[CH3:1][C@H:2]1[C@H:3]2[C@H:4]3[C@:8]([CH3:9])([CH2:10][CH2:11][C@@H:12]2[C:13]2[CH:14]=[CH:15][C:16]([OH:20])=[CH:17][C:18]=2[CH2:19]1)[C:7](=[O:22])[CH2:6][CH2:5]3
Reactant: C[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Temperature: 60 °C
Yield: 82 %

Procedure:
To a solution of 114 g of 7α-methylandrost-4-ene-3,17-dione 45a in 1,500 mL of glacial acetic acid was added 106 g of CuCl2. The mixture with stirring was heated to 60° C. for 72 h. The reaction mixture was poured into H2O (500 mL reaction mixture to 3,500 mL H2O) and the precipitate collected by filtration and air dried for 18 h. The solid was dissolved in methylene chloride (2 L) and washed with sat. NaHCO3 (2 L), H2O (2 L), and sat. NaCl (2 L). The methylene chloride solution was dried over MgSO4, and filtered. The methylene chloride solution was filtered (suction chromatography) through 1.5 kg of flash chromatography silica gel 60 (230-400 mesh). The pad of silica gel was further eluted with additional MeCl2. The MeCl2 solutions were combined and then treated with Norite, filtered through a pad of celite and then after evaporation at reduced pressure there was obtained 91.3 g of pure 13 (82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1C(O)=O>CS(C)=O.CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[N:14]3[CH2:21][CH2:20][CH2:19][C@H:15]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: O=C1Nc2cccc(Cl)c2C(=O)N2CCC[C@@H]12

Procedure:
10 g (50.6 mmol) of 6-chloroisatoic acid anhydride are stirred at 110° C. for 2 hours with 5.82 g (50.6 mmol) of L-proline in 80 ml of dimethyl sulphoxide. The solution is evaporated and the residue is crystallised from ethyl acetate. There is obtained (S)-6-chloro-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione of melting point 264°-266° C. (b) A solution of 4.0 g (16 mmol) of (S)-6-chloro-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10)-dione in 30 ml of dimethylformamide is treated under an argon atmosphere with 0.57 g (16 mmol) of sodium hydride (60 percent oil dispersion) and stirred at room temperature for 1 hour. 3.02 g (17.5 mmol) of diethylchlorophosphate are added dropwise to the thus-obtained suspension at -20° C. and the mixture is stirred at this temperature for 10 minutes.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH2:18][CH2:19][O:20][CH2:21][CH:22]=3)=[C:13]([F:23])[CH:12]=2)[CH2:6]1.C[C:25]1[O:26][C:27]([CH:30]=S(=O)=O)=[N:28][N:29]=1.O>CS(C)=O>[CH3:30][C:27]1[O:26][C:25]([O:3][CH2:4][C@@H:5]2[O:9][C:8](=[O:10])[N:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH2:18][CH2:19][O:20][CH2:21][CH:22]=4)=[C:13]([F:23])[CH:12]=3)[CH2:6]2)=[N:29][N:28]=1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCOCC2)c(F)c1
Reactant: Cc1nnc(C=S(=O)=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nnc(OC[C@H]2CN(c3ccc(C4=CCOCC4)c(F)c3)C(=O)O2)o1
Temperature: 110 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
Sodium hydride (28 mg of a 60% suspension in mineral oil, 0.69 mmol) was added to a solution of 5(R)-hydroxymethyl-3-(4-[3,6-dihydro-(2H)-pyran-4-yl]-3-fluorophenyl)oxazolidin-2-one (0.2 g, 0.69 mmol) in DMSO (5 ml) and the mixture was stirred for 1 hour. 2-Methyl-5-sulfonylmethyl-1,3,4-oxadiazole (RB Woodward et al, (Journal of the American Chemical Society 105, 904 [1983]) (0.11 g, 0.69 mmol) was added and the solution heated at 110° C. for 9 hours. Water (40 ml) was added and the mixture extracted three times with EtOAc. The combined extracts were dried by filtration through phase separation paper (Whatman 1PS) and evaporated. The residue was purified by flash column chromatography, eluting first with EtOAc and then with EtOAc/MeOH (20:1) to give the title product (23 mg, 9%) as a solid (mp 146-147° C.). MS: 376 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:35][CH2:36][CH2:37]Br>O1CCCC1>[Br:35][CH2:36][CH2:37][N:10]1[CH:11]=[C:12]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:25][CH:26]([F:28])[F:27])=[N:9]1
Reactant: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C(Nc1cn(CCBr)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 70 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
A mixture of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (3.00 g, 7.41 mmol), Cs2CO3 (9.90 g, 30.38 mmol), tetrahydrofuran (90 mL), 1,2-dibromoethane (7.00 g, 37.26 mmol) was stirred at 70° C. for 3 hours in an oil bath. The mixture was allowed to cool to ambient temperature then concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with ethyl acetate/petroleum ether (1:1) to afford N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-pyrimidine-3-carboxamide as a off-white solid (2.2 g, 58%). TLC: Rf=0.6; ethyl acetate/petroleum ether=1:1; LCMS (Method 14) [M+H]+=513.2, RT=1.03 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[O:23][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)COc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 80.6 %

Procedure:
2,4-Dibenzyloxyphenol (3.1 g) is added to a stirred suspension of sodium hydride (0.44 g, 60% dispersion in mineral oil) and the mixture is heated at reflux for 30 minutes. Refluxing is allowed to abate when ethyl bromoacetate (1.8 g) is added and the mixture heated at reflux for 1 hour. The reaction mixture is evaporated and the residue partitioned between ethyl acetate and water. The organic phase is washed with water, dried over magnesium sulphate and evaporated to give a light brown oil which is purified by column chromatography on silica eluting with dichloromethane. Fractions homogeneous in the required product are combined and evaporated. The residue is triturated with pentane to give ethyl (2,4-dibenzyloxyphenoxy)acetate (3.2 g) as a white powder, m.p. 62-64° C. [Elemental analysis:- C,73.3; H,6.13%. Calculated:- C,73.5; H,6.13%].
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:31])[C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=1[C:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:14]=2[CH3:15])[CH2:17][CH2:18]1)=[O:31]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)c3c(Cl)cccc3Cl)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(C(=O)c2c(Cl)cccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[1-(2,6-dichloro-benzoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (96 mg, 0.197 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (94.2 mg, 2.2 mmol) in water (2 mL). The reaction mixture was stirred at room temperature overnight. After this time, the reaction mixture was concentrated. Water (˜20 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (3.9 mL). The resulting white precipitate was collected by vacuum filtration, washed with hexanes, and then further dried under vacuum to {4-[1-(2,6-dichloro-benzoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (66 mg, 71%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.84-7.97 (m, 2H), 7.68 (s, 1H), 7.55-7.66 (m, 2H), 7.44-7.53 (m, 1H), 7.34 (s, 1H), 4.69-4.80 (m, 1H), 3.76 (br. s., 2H), 3.32 (br. s., 6H), 2.43 (s, 2H), 1.57-1.85 (m, 2H). MS cald. for C25H23Cl2FNO3 [(M+H)+]: 474, obsd. 474.1.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH2:1]=[C:14]1[CH2:15][CH2:16][C:11]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:12][CH2:13]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 112.6 %

Procedure:
To a solution of methyl triphenylphosphonium bromide (13.7 g) in DMSO (140 ml) was added potassium tert-butoxide (4.31 g) under ice-cooling and the mixture was stirred for 1.5 hours at ambient temperature. After cooling, 1,4-dioxaspiro[4,5]decan-8-one (5.0 g) was dropwise added to the solution under ice-cooling and then stirred for 1 hour at room temperature. The reaction mixture was poured into water (300 ml) and extracted twice with ethyl acetate (150 ml). The extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give a residue. The residue was washed with a mixture of hexane and ethyl acetate (5:1 v/v) (300 ml). The resulting precipitates were collected and were chromatographed on silica gel (500 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 8-methylene 1,4-dioxaspiro[4,5]decane (5.56 g).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH2:32]O)=[CH:31][C:26]=2[O:25][CH2:24]1>>[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH2:32][O:22][C:19]3[CH:18]=[CH:17][C:16]([C:13]4[N:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][N:14]=4)=[CH:21][CH:20]=3)=[CH:31][C:26]=2[O:25][CH2:24]1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: CCCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCCCCOc1cnc(-c2ccc(OCc3ccc4c(c3)OCO4)cc2)nc1

Procedure:
By Mitsunobu etherification of 4-(5-octyloxypyrimidin-2-yl)phenol using benzo[1,3]dioxol-5-ylmethanol analogously to Example 208.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[NH2:14])=[CH:11][C:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[NH:14][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:11][C:10]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Product: CC(=O)c1c(NS(C)(=O)=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O

Procedure:
The product of Example 2 was reacted with methanesulfonyl chloride using the conditions of EXAMPLE 11 to afford the title compound. HPLC/MS: 549.9 (M+1), 551.9 (M+3); Rt=4.24 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.S(OC)(O[CH3:14])(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:14])=[CH:4][C:3]=1[CH3:9]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(O)ccc1Cl
Product: COc1ccc(Cl)c(C)c1

Procedure:
4-Chloro-m-cresol was methylated with dimethyl sulfate to give 1-chloro-4-methoxy-2-methylbenzene. This was converted with N -bromosuccinimide into 2-bromomethyl- 1-chloro-4-methoxybenzene. Subsequent alkylation with diethyl malonate yielded diethyl (2-chloro -5-methoxy-benzyl)-malonate. This was condensed with morpholine -formamidine in analogy to Example 1, part d), to give 5-(2-chloro-5-methoxy-benzyl)-2-(morpholin-4-yl)-4,6(1H,5H)-pyrimidinedione. Subsequent chlorination with POCl3 analogously to Example 1e) gave 4,6-dichloro-5-(2-chloro-5-methoxy-benzyl)-2-(morpholin-4-yl)-pyrimidine which was reacted further with (4-tert.butylbenzenesulfonamide) K analogously to Example 1 g) to give 4-tert-butyl-N-[6-chloro-5-(2-chloro -5 -methoxy-benzyl)-2-(morpholin-4-yl)-pyrimidin-4-yl]benzenesulfonamide. Subsequent reaction with sodium ethylene glycolate analogously to Example 1h) finally gave 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-chloro-5-methoxybenzyl)-2-(morpholine-4-yl)pyrimidin-4-yl]-benzenesulfonamide. M.p. 159°-162° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:24][C@@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4].[C:25]([Zn]C#N)#[N:26]>CC(N(C)C)=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>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:24][C@@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[CH:21][C:20]([C:25]#[N:26])=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: CC(C)(CO)NC(=O)c1nn(-c2ccc(Br)cn2)c2c1C[C@@H]1C[C@H]21
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CC(C)(CO)NC(=O)c1nn(-c2ccc(C#N)cn2)c2c1C[C@@H]1C[C@H]21
Temperature: 140 °C
Yield: 63.9 %

Procedure:
In a heavy-walled sealed tube with a stir bar were added (1aS,5aS)-2-(5-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (0.020 g, 0.051 mmol), tetrakis(triphenylphosphine)palladium(0) (0.012 g, 0.010 mmol), and dicyanozinc (0.012 g, 0.10 mmol) in DMA (1.2 mL). The tube was sealed, flushed with argon, and heated under microwave irradiation at 140° C. for 90 min. Ice water (10 mL) was added. The mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (4 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (EtOAc/Hexanes) to give the title compound (0.011 g) as a white solid. LCMS m/z=338.5 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.47 (td, J=4.8 and 3.5 Hz, 1H), 1.26-1.33 (m, 1H), 1.43 (s, 6H), 2.27-2.35 (m, 1H), 2.79-2.86 (m, 1H), 2.92 (d, J=16.5 Hz, 1H), 3.02 (dd, J=16.7 and 6.4 Hz, 1H), 3.71 (s, 2H), 6.88-6.94 (bs, 1H), 8.03-8.09 (m, 2H), 8.74-8.77 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:29][C:11]3=[N:12][C:13]([N:22]([CH2:27]C)[S:23]([CH3:26])(=[O:25])=[O:24])=[C:14]([CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[CH:15]=[C:10]3[C:9]=2[C:30](=[O:33])[NH:31][CH3:32])=[CH:4][CH:3]=1.[CH3:34][O:35][C:36]([C@@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1)=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:29][C:11]3=[N:12][C:13]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])=[C:14]([CH2:16][CH2:17][CH2:18][C:19]([N:39]4[CH2:40][CH2:41][CH2:42][C@H:38]4[C:36]([O:35][CH3:34])=[O:37])=[O:20])[CH:15]=[C:10]3[C:9]=2[C:30](=[O:33])[NH:31][CH3:32])=[CH:4][CH:3]=1
Reactant: CCN(c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1CCCC(=O)O)S(C)(=O)=O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(CCCC(=O)N3CCC[C@H]3C(=O)OC)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-ethylmethylsulfonamido)furo[2,3-b]pyridin-5-yl)butanoic acid (15 mg) in DMF (1 ml) is added (S)-methylpyrrolidine-2-carboxylate (4.2 mg), HATU (18.5 mg) and DIPEA (17 μl), and the mixture is stirred at rt for 30 min, and purified by preparative HPLC to afford the title compound. (M+H)+=575.2; Retention time=1.26 min, Method A. 1H NMR (400 MHz, CD3CN) δ ppm 8.18 (m, 1H), 8.06-8.01 (m, 2H), 7.33-7.26 (m, 2H), 6.91 (br s, 1H), 4.33-4.29 (m, 1H), 3.67 (s, 3H), 3.61-3.50 (m, 2H), 3.27 (s, 3H), 3.16 (s, 3H), 2.98-2.90 (m, 2H), 2.92 (d, 3H), 2.51-2.36 (m, 2H), 2.32-1.78 (m, 6H)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:29][C:12]2=[CH:13][C:14]3[C:15](=[O:28])[N:16]([CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[CH2:38][CH:39]([NH2:41])[CH3:40].C(N(CC)C(C)C)(C)C>C(O)CCC>[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[CH2:38][CH:39]([NH:41][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:29][C:12]2=[CH:13][C:14]3[C:15](=[O:28])[N:16]([CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1)[CH3:40]
Reactant: CN1CCC(N2C(=O)c3cc4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Reactant: CC(N)Cc1cc(F)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Yield: 83.8 %

Procedure:
2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)-imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.59 g, 1.43 mmol), 1-(2,5-difluorophenyl)propan-2-amine (0.29 g, 1.72 mmol), n-butanol (50 mL) and N,N-diisopropylethylamine (5 mL) were mixed together in a flask. The reaction mixture was stirred and heated to reflux overnight undr argon. Solvents were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a bown solid product, 0.65 g, 83.8% yield. MS: 540.8 [M−H]−. 1H-NMR (DMSO-d6, 300 MHz): δ 13.42 (s, 1H), 11.26 (s, 1 Hz), 10.86 (d, 1H, J=8.0 Hz), 8.12 (s, 1H), 8.01 (s, 1H), 7.32-7.31 (m, 1H), 7.24-7.21 (m, 1H), 7.13-7.11 (m, 1H), 6.88-6.84 (m, 1H), 6.14 (d, 1H, J=7.5 Hz), 4.19-4.14 (m, 2H), 3.37-3.33 (m, 3H), 3.15 (m, 2H), 3.01-2.99 (m, 2H), 2.49 (s, 3H), 2.34 (s, 3H), 1.78-1.77 (m, 2H), 1.33 (d, 3H, J=6.5 Hz).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:19]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([C:14](Cl)=[O:15])[O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].[N-:27]=[N+:28]=[N-:29].[Na+]>O1CCCC1>[CH3:1][S:2]([NH:5][C:6]1[C:19]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([C:14]([N:27]=[N+:28]=[N-:29])=[O:15])[O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)Nc1cc2oc(C(=O)Cl)cc(=O)c2cc1Oc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc2oc(C(=O)N=[N+]=[N-])cc(=O)c2cc1Oc1ccccc1
Reaction time: 1.5 h
Yield: 46 %

Procedure:
3.1 g of 7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one-2-carboxylic acid chloride was dissolved in 80 ml of anhydrous tetrahydrofuran. This solution was dropwise added to 10 ml of an aqueous solution containing 1.26 g of sodium azide in 10 minutes at 5°-10° C. The mixture was stirred for 1.5 hours at 10°-20° C. The resulting crystal was collected by filtration to obtain 1.45 g (yield: 46%) of 7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one-2-carboxylic acid azide having a melting point of 146°-149° C. (decomposed).
Reaction SMILES: B.C1COCC1.[OH:7][CH2:8][CH:9]([C:14]([F:21])([N+:18]([O-:20])=[O:19])[N+:15]([O-:17])=[O:16])[CH2:10][C:11](O)=[O:12]>O>[F:21][C:14]([N+:18]([O-:20])=[O:19])([N+:15]([O-:17])=[O:16])[CH:9]([CH2:10][CH2:11][OH:12])[CH2:8][OH:7]
Reactant: O=C(O)CC(CO)C(F)([N+](=O)[O-])[N+](=O)[O-]
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])C(F)(C(CO)CCO)[N+](=O)[O-]
Reaction time: 24 h
Yield: 100.2 %

Procedure:
To a 1M solution of borane-THF (5 ml, 5 mmole) stirred under a nitrogen atmosphere in an ice bath was added 1.0 g (4.8 mmole) of 4-hydroxy-3-(fluorodinitromethyl)butyric acid, gamma-lactone. The solution was then held in a water bath at 25°-28° C. for 24 hr. before 1 ml of water was slowly added dropwise. The solution was poured into 15 ml of water and extracted with ether to give 1.02 g (100%) of an oil which was essentially pure by TLC. Chromatography on silica gel 60 using methylene chloride-acetone (80/20) as eluent gave an analytical sample. 1H NMR (CDCl3) 1.70-1.93 (m, 2H), 2.36(OH), 3.34-3.97 (m, 5H); IR (film) 3700-3050 (OH), 1605 (NO2) cm-1.