Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[O:12][C:11](=[O:13])[CH:10]=[C:9]([OH:14])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37][C:10]1[C:11](=[O:13])[O:12][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:8][C:9]=1[OH:14])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(C2CCCCC2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(C3CCCCC3)OC2=O)c(C(C)(C)C)cc1CO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The title compound was prepared as described in General Method 9 from 6-cyclohexyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example NN; 156 mg, 0.499 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF; 250 mg, 0.546 mmol), K2CO3 (303 mg, 2.195 mmol), and DMF (4 mL). The reaction was stirred at room temperature for 2.5 hours and then worked up in the usual manner. The crude product was flash chromatographed using CH2Cl2 : MeOH (98:2) to give the desired product as a solid, m.p. 138-139° C. (dec.). 1H NMR (CDCl3) δ 1.0-2.1 (m, 13 H), 1.58 (s, 9 H), 2.03 (s, 3 H), 2.6-2.7 (m, 3 H), 3.05 (d, 1 H), 4.6 (s, 2 H), 6.69-6.74 (d, s, 3 H), 6.98 (d, 2 H), 7.34 (s, 1 H), 7.74 (s, 1 H).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](O)=[O:8])=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([Cl:18])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-c2ccccc2)cc1

Procedure:
Heated at reflux for 2 hrs., a solution of 25 g (0.13 mole) of 4-biphenylcarboxylic acid, in 125 ml of thionyl chloride. Distilled to remove the excess thionyl chloride, then added 150 ml of AR toluene. Evaporated in vacuo to give a brown solid, 27 g, m.p. softens 107°, some melts 109°-112°, darkens 370°, melts >400°.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[N:17]1([CH2:21][C@@H:22]([NH2:32])[C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:21][C@@H:22]([NH:32][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)c1ccc([C@H](N)CN2CCC2)cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CC(C)c1ccc([C@@H](CN2CCC2)Nc2ncnc3c(C(N)=O)ccnc23)cc1

Procedure:
Compound 37 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-2-Azetidin-1-yl-1-(4-isopropyl-phenyl)-ethylamine dihydrochloride to give the title compound as an off-white solid. LC/MS [391 (M+H)]; 1H NMR (500 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.38-8.87 (m, 2H), 8.53 (s, 1H), 8.37 (d, J=4.4 Hz, 1H), 8.17 (s, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.17 (d, J=8.0 Hz, 2H), 5.60-4.97 (m, 1H), 3.16-2.99 (m, 5H), 2.89-2.77 (m, 1H), 2.74 (dd, J=11.9, 4.9 Hz, 1H), 2.02-1.72 (m, 2H), 1.16 (d, J=6.8 Hz, 6H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:14][Si:15](Cl)([CH3:17])[CH3:16]>C1COCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:13]=[CH:12][C:10]([N:11]([Si:15]([CH3:17])([CH3:16])[CH3:14])[Si:15]([CH3:17])([CH3:16])[CH3:14])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: C[Si](C)(C)Cl
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Product: C[Si](C)(C)N(c1ccc(N2CCOCC2)cc1)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73 %

Procedure:
4-Morpholinoaniline (1 g, 5.61 mmol) was dissolved in dry THF (25 ml). N-BuLi (1.41M, 8.8 ml) was added dropwise at 0° C. over 5 minutes and the solution changed from brown to yellow. After stirring for 2.5 hours while warming to room temperature, trimethylsilyl chloride (97%, 1.62 ml) was added, followed by stirring at room temperature for 12 hours. Evaporation of the solvent gave a yellow solid which was sublimed at 10-4 torr to produce pure 4-morpholino-N,N-bistrimethylsilyl aniline as white solid (1.32 g, 73%). 1H NMR (CDCl3) 6.75 (s, Ph, 4H), 3.81 (t, CH2, 4H), 3.05 (t, CH2, 4H), 0.03 (s, TMS, 18H) .
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].C(OC([NH:23][C@H:24]([C:32](O)=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)(C)(C)C.P(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[NH2:23][C@@H:24]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]([NH:6][C:5]1[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 101.9 %

Procedure:
A mixture of 3,5-bis(trifluoromethyl)aniline (0.20 g, 0.87 mmol), N-(tert-butoxycarbonyl)-L-phenylalanine (254.8 mg, 0.96 mmol), phosphorus trichloride (40 μL, 0.46 mmol) and toluene (4 mL) was stirred at 80° C. for 1.5 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was crystallized by isopropyl ether/n-hexane to give the title compound (333.7 mg, 92.9%) as an yellow white powder.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[C:17]([C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)([O:19][CH2:20][CH3:21])=[O:18]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[C:17]([C:22]1[CH:27]=[CH:26][C:25]([C:9]2[CH2:10][C:11]3[C:16]([CH:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:24][CH:23]=1)([O:19][CH2:20][CH3:21])=[O:18]
Reactant: C1=Cc2ccccc2C1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1ccc(C2=Cc3ccccc3C2)cc1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 5.52 g (20 mmole) of para-carbethoxy iodo-benzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 mnl of ethanol. The crystalline precipitate was isolated, washed with cold ethanol and dried under vacuum to obtain 3.1 g (59%) of 2-(4-carbethoxy-phenyl)-indene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([F:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:41].[CH3:42][NH:43][CH3:44]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:43]([CH3:44])[CH3:42])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([F:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:41]
Reactant: Cc1ccc(C(=O)Nc2ccc(C)c(-c3nc(S(C)(=O)=O)nc4c3CNC(=O)N4c3c(F)cccc3F)c2)cc1F
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(C)c(-c3nc(N(C)C)nc4c3CNC(=O)N4c3c(F)cccc3F)c2)cc1F
Reaction time: 72 h

Procedure:
To the compound N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide (0.075 g, 0.129 mmol) in THF (4 mL) was added a 1.0 M solution of dimethylamine in THF (0.322 mL, 0.322 mmol). The mixture was stirred under argon for 3 days. The completed reaction mixture was diluted with EtOAc and the organic phase washed with water, brine (2×), dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel, eluting with 1% MeOH/CH2Cl2 to afford the title compound as a white solid. mp 257.8-264.3° C.; LC-MS m/z 547 (M+H)+, 2.24 min (ret. time).
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[C:8]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)=[N:7][O:6][CH:5]=2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][C:5](=[O:6])[C:4]1[C:3]([CH2:1][CH3:2])=[CH:11][C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:8]=1[NH2:7])[CH3:22]
Reactant: CCc1cc([N+](=O)[O-])cc2nocc12
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1c(N)cc([N+](=O)[O-])cc1CC

Procedure:
4-ethyl-6-nitro anthranil (2 g) was refluxed for three hours in ethanol with potassium carbonate. The reaction mixture was cooled, filtered and evaporated to a dark oily solid which was dissolved in ethyl acetate and dried. The residue was re-dissolved in methylene chloride and columned on silica gel using 15% ethyl acetate-petroleum ether. The residue from the filtrate was recrystallized from methylene chloride-petroleum ether to give 1.9 g ethyl-2-amino-6-ethyl-4-nitrobenzoate, m.p. 68°-70° C., IR: 3490 cm-1, 3380 cm-1, 3080 cm-1, 2980 cm-1, 1690 cm-1, 1620 cm-1, 1515 cm-1, 1350 cm-1.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[C-:16]#[N:17].[K+]>CN(C=O)C>[C:16]([CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:17]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O)(CC#N)CC1

Procedure:
A solution of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (2 g) in DMF (20 mL) was treated with potassium cyanide (0.672 g) and the resultant mixture stirred at 20° C. for 4 days. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 60% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.18 g.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][CH2:6][CH2:7][N:8]=[C:9]=[O:10]>C1COCC1>[Cl:5][CH2:6][CH2:7][NH:8][C:9]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:10]
Reactant: NC1CC1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: O=C(NCCCl)NC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of cyclopropanamine (0.541 g, 9.48 mmol) in THF (10 mL) was treated with chloroethylisocyanate (1.0 g, 9.48 mmol), stirred at RT for 2 h, then concentrated to dryness and treated with MeCN. The resulting solid was collected via filtration and dried to afford 1-(2-chloroethyl)-3-cyclopropylurea (1.31 g, 85%). 1H NMR (400 MHz, DMSO-d6): δ 6.28 (s, 1 H), 6.12 (br s, 1 H), 3.55 (t, J=6.4 Hz, 2 H), 3.30 (m, 2 H), 2.36 (m, 1 H), 0.55 (m, 2 H), 0.31 (m, 2 H); MS (ESI) m/z: 162.9 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[CH:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][CH2:18][O:19][C:20](/[C:22](/Cl)=[N:23]\[OH:24])=[O:21].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.Cl>[CH2:18]([O:19][C:20]([C:22]1[CH:15]=[C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16])[CH:9]=2)[O:24][N:23]=1)=[O:21])[CH3:17]
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: CCOC(=O)/C(Cl)=N\O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2cccc(NC(=O)OC(C)(C)C)c2)on1
Reaction time: 16 h
Yield: 69.7 %

Procedure:
(3-ethynyl-phenyl)-carbamic acid tert-butyl ester (2.48 g, 0.0114 mole) and ethyl chlorooximidoacetate (3.82 g, 0.0252 mole) were mixed in THF (12 mL) and triethylamine (3.98 mL, 0.0286 mole) was added slowly. The mixture was stirred for 16 hours and then diluted with ethyl acetate (100 mL) and aqueous 1N HCl (50 mL). The two layers were separated and the aqueous layer extracted with ethyl acetate (2×50 mL). The combined organics were dried over anhydrous Na2SO4, filtered, concentrated in vacuo and purified by flash chromatography (10–15% ethyl acetate/Hexane) to provide the titled compound (2.64 g, 50% yield).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH:1]1([O:7][N:9]2[C:13](=[O:14])[C:12]3[C:11](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]2=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A solution of triphenylphosine (15.53 g, 59.2 mmol), cyclohexanol (6.25 mL, 59.2 mmol), and N-hydroxypthalimide (9.66 g, 59.2 mmol) in anhydrous tetrahydrofuran (500 mL) under Argon was treated dropwise over approximately 20 minutes with a solution of di-tert-butyl azodicarboxylate (15.00 g, 65.14 mmol) in tetrahydrofuran (100 mL) with a water bath to control the exotherm. After the reddish color had dissipated, a mixture of di-tert-butyl azodicarboxylate (3.00 g, 13.0 mmol) and triphenylphosine (3.11 g, 11.8 mmol) in anhydrous tetrahydrofuran (50 mL) was added to the reaction mixture and allowed to stir overnight at ambient temperature. After evaporation in vacuo, the residue was treated with trifluoroacetic acid (100 mL) and stirred for 20 minutes. The reaction was evaporated in vacuo and the residue was partitioned between water and dichloromethane. The layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue. The crude material was purified twice by flash silica gel chromatography eluting with hexane:ethyl acetate (4:1 and 9:1). Pure fractions were concentrated in vacuo to a solid and dried under high vacuum to provide 2-(cyclohexyloxy)-1H-isoindole-1,3(2H)-dione as a solid (10.90 g, 75%).
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[C:37]1([S:43]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([N+:52]([O-])=O)[CH:46]=2)=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:37]1([S:43]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([NH2:52])[CH:46]=2)=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=[N+]([O-])c1cc(S(=O)c2ccccc2)ccc1Cl
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Nc1cc(S(=O)c2ccccc2)ccc1Cl
Yield: 90 %

Procedure:
Following the procedure described in Example 40 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of phenyl-(4-chloro-3-nitrophenyl) sulfoxide, the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]2[O:10][CH:9]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH2:8][CH2:7][C:6]=2[CH:19]=1.CO[CH:23]1[CH2:27][CH2:26][CH:25](OC)O1.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH:23]=[CH:27][CH:26]=[CH:25]2)[C:5]2[O:10][CH:9]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH2:8][CH2:7][C:6]=2[CH:19]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1cc(F)cc2c1OC(COC1CCCCO1)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: Fc1cc2c(c(-n3cccc3)c1)OC(COC1CCCCO1)CC2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
A mixture of intermediate 16-b (0.036 mol), 2,5-dimethoxytetrahydrofuran (0.22 mol) and PTSA (catalytic quantity) in DMF (140 ml) was stirred for 90 min at 100° C. The solvent was evaporated. The residue was dissolved in CH2Cl2. The organic solution was washed once with water, dried (MgSO4), filtered and the solvent was evaporated The residue was purified by column chromatography over silica gel (eluent: CH2Cl2). The pure fractions were collected and the solvent was evaporated, yielding 6.6 g (55.3%) of (±)-6-fluoro-3,4-dihydro-8-(1H-pyrrol-1-yl)-2-[[(tetrahydro-2H-pyran-2-yl)oxy]-methyl]-2H-1-benzopyran (interm. 17-b).
Reaction SMILES: CS[CH2:3][C:4](=[O:15])[C:5]([N+:12]([O-:14])=[O:13])=[C:6]1[NH:11][CH2:10][CH2:9][CH2:8][S:7]1.CC[C:18](Cl)=[S:19].[CH3:21]CCCC(Cl)=S.CCCC(Cl)=S>>[CH3:21][S:19][CH2:18][CH2:3][C:4](=[O:15])[C:5]([N+:12]([O-:14])=[O:13])=[C:6]1[NH:11][CH2:10][CH2:9][CH2:8][S:7]1
Reactant: CSCC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Reactant: CCCCC(=S)Cl
Reactant: CCC(=S)Cl
Agent: CCCC(=S)Cl
Product: CSCCC(=O)C(=C1NCCCS1)[N+](=O)[O-]

Procedure:
In a similar manner, 3-(methylthio)-1-nitro-1-(tetrahydro-2H-1,3-thiazin-2-ylidene)-2-propanone (18) was prepared as a yellow solid, m.p.: 117.5°-119°, from methylthioacetyl chloride; 5-(methylthio)-1-nitro-1-(tetrahydro-2He1,3-thiazin-2-ylidene)-2-pentanone (19) was prepared as a pale yellow solid, m.p.: 49°-49.5°, from 4-methylthiobutyryl chloride; 4-(methylthio)-1-nitro-1-(tetrahydro-2H-1,3-thiazin-2-ylidene)-2-butanone (20) was prepared as a yellow solid, m.p.: 42°-43° from 3-methylthiopropionyl chloride.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16])[CH3:10].Cl>CCOCC>[CH2:9]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]([OH:16])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:10]
Reactant: CCOc1cccc(C=O)c1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCOc1cccc(C(O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 242.5 %

Procedure:
To an ether solution of phenylmagnesium bromide [prepared from bromobenzene (3.69 ml, 35 m mol), magnesium (0.95 g, 39 m mol) and ether (50 ml)], an ether solution (30 ml) of 3-ethoxybenzaldehyde (3.0 g, 20 m mol) was added dropwise thereto with stirring and under cooling with ice. After 30 minutes, 1 N hydrochloric acid (20 ml) was added thereto. The ether layer was separated and the aqueous layer was extracted with ether (20 ml). After the combined ether layer was washed with a saturated aqueous solution of sodium chloride (15 ml) and dried, the solvent was distilled off under reduced pressure. The resulting residue was subjected to chromatography on silica gel (100 g) using hexane, and eluted with hexane and then with hexane-ethyl acetate (5:1). The resulting yellow oily material containing the desired compound was distilled to obtain the desired compound (2.9 g, 60%) as a colorless oily material (150-153° C./1-2 mmHg).
Reaction SMILES: [C:1]([N:4](C)[NH:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2].Cl.CNNC[C:20](O)=[O:21].C([O:25]P([O-])OCC)C>>[C:2]([CH2:1][NH:4][NH:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])([O:21][CH3:20])=[O:25]
Reactant: CNNCC(=O)O
Reactant: CCOP(=O)(NN(C)C(C)=O)OCC
Reactant: CCOP([O-])OCC
Agent: Cl
Product: CCOP(=O)(NNCC(=O)OC)OCC

Procedure:
This compound was synthesized in a similar manner to the compound of Example 5, except that methylhydrazinoacetate hydrochloride was used in place of 1-acetyl-1-methyl hydrazine and diethylphosphite was used in place of dimethylphosphite. A colorless oil was obtained which was subsequently distilled at 115° C./0.05 mm. to yield the desired product, nD27 =1.4342.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]([NH:17]S(C(C)(C)C)=O)[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:7]([O:24][CH3:25])[N:6]=[CH:5][N:4]=1.[ClH:26].O1CCOCC1>CO>[ClH:26].[NH2:17][CH:9]([C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[N:6][C:7]=1[O:24][CH3:25])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)ncnc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CCCC(N)c1c(OC)ncnc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) slightly yellow solution of methyl 5-(4,6-dimethoxypyrimidin-5-yl)-5-(1,1-dimethylethylsulfinamido)pentanoate (178 mg; 0.47 mmol) in MeOH (4 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (0.24 ml; 0.96 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 5 h. The reaction mixture was then concentrated to dryness under reduced pressure and the yellow oily residue was further dried under HV to give methyl 5-amino-5-(4,6-dimethoxypyrimidin-5-yl)pentanoate HCl salt as a yellow solid. LC-MS (conditions A): tR=0.41 min.; [M+H]+: 270.10 g/mol.
Reaction SMILES: [CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9](B4OC(C)(C)C(C)(C)O4)[CH:10]=3)[C:5]2=[O:22])[CH2:3][CH2:2]1.Br[C:24]1[CH:38]=[CH:37][C:27]([CH2:28][N:29]2[C:33](=[O:34])[CH2:32][N:31]([CH3:35])[C:30]2=[O:36])=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(Cl)Cl.O>[CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:24]4[CH:38]=[CH:37][C:27]([CH2:28][N:29]5[C:33](=[O:34])[CH2:32][N:31]([CH3:35])[C:30]5=[O:36])=[CH:26][CH:25]=4)[CH:10]=3)[C:5]2=[O:22])[CH2:2][CH2:3]1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Reactant: CN1CC(=O)N(Cc2ccc(Br)cc2)C1=O
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CC(=O)N(Cc2ccc(-c3ccc4c(c3)CN(C3CC3)C4=O)cc2)C1=O
Yield: 2280.8 %

Procedure:
2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (1A5) (0.08 mmol, 26.4 mg), 3-(4-bromobenzyl)-1-methylimidazolidine-2,4-dione (3D3) (0.08 mmol, 25.0 mg), tris(dibenzylidineacetone)dipalladium (0.004 mmol, 4.12 mg), tricyclohexylphosphine (0.096 mmol, 3.1 mg) and potassium phosphate (0.16 mmol, 39.0 mg) were suspended in dioxane (1 ml) and water (0.5 ml) and heated at 120° C. in the microwave for 20 min. The reaction was diluted with DCM (2 ml) and water (2 ml) then passed through a hydrophobic fritted tube. The organic phase was concentrated and the residue purified on basic HPLC to give 3-(4-(2-cyclopropyl-1-oxoisoindolin-5-yl)benzyl)-1-methylimidazoline-2,4-dione (Example 3a) (685 mg, 55%) 1H NMR (400 MHz, CDCl3) δ 7.87 (d, 1H) 7.64 (d, 1H) 7.57-7.50 (m, 5H) 4.71 (s, 2H) 4.37 (s, 2H) 3.89 (s, 2H) 3.01 (s, 3H) 2.95 (m, 1H) 0.95-0.88 (m, 4H) LCMS m/z (M+H) 376.0.
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O.[Cl:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=1[O:40][CH:41]([CH3:43])[CH3:42])/[C:33](=[N:35]/O)/[NH2:34]>CN(C=O)C>[Cl:29][C:30]1[CH:31]=[C:32]([C:33]2[N:35]=[C:9]([C:8]3[CH:7]=[CH:6][C:5]([S:1]([NH2:2])(=[O:3])=[O:4])=[CH:13][CH:12]=3)[O:11][N:34]=2)[CH:37]=[CH:38][C:39]=1[O:40][CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(S(N)(=O)=O)cc3)n2)cc1Cl
Temperature: 140 °C
Yield: 50 %

Procedure:
To a slurry of 4-sulfamoylbenzoic acid (1.452 g, 7.22 mmol) in DMF (8.20 ml) was added EDC (1.383 g, 7.22 mmol) followed by HOBT hydrate (0.975 g, 7.22 mmol). After about 30 minutes a solution of (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide in DMF (8.20 ml) was added. The reaction mixture was heated to about 140° C. for about 2 h. After cooling to room temperature the reaction mixture was concentrated in vacuo and purified by purified by chromatography on silica gel (eluting with EtOAc/Hep) to provide 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzenesulfonamide (1.28 g, 50%) as a colorless solid. LCMS (Table 1, Method c) Rt=2.74 min, m/z 392 (M−H)−.