Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([O:20]CC)=O)[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>ClCCl.O>[CH2:23]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([NH:30][CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:20])[NH:15][C:14]=12)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Reactant: NCc1cccnc1
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1cccnc1)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Temperature: 100 °C
Yield: 49.6 %

Procedure:
A mixture of ethyl 7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (Reference Example 3) (634 mg, 1.64 mmol) and 3-(aminomethyl)pyridine (3.8 mL, 37 mmol) was heated neat at 100° C. for 72 h under N2. The mixture was cooled to room temperature and diluted with dichloromethane (150 mL) and water (100 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel, gradient 50-70% ethyl acetate/hexanes) to provide 7-(dibenzylamino)-N-(3-pyridinylmethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (364 mg, 49%) as an orange solid: Rf 0.08 (75:25 ethyl acetate/hexanes); mp 105-108° C.; 1H NMR (300 MHz, CDCl3) δ4.60 (2H, d, J=6.0 Hz), 4.89 (4H, s), 6.50 (1H, t, J=5.4 Hz), 6.71 (1H, s), 6.99 (1H, d, J=5.6 Hz), 7.28-7.31 (2H, m), 7.34-7.42 (9H, m), 7.64 (1H, d, J=7.8 Hz), 7.89 (1H, d, J=5.6 Hz), 8.55 (2H, s), 8.97 (1H, s); ESI MS m/z 448 [C28H25N5O+H]+; HPLC (Method A) >99% (AUC), tR=13.02 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][CH3:22])[CH:17]=2)[CH:12]([C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH:11]1[C:32]([O:34][CH3:35])=[O:33].[H-].[Na+].Br[CH2:39][CH2:40][CH2:41][OH:42]>CN(C=O)C>[OH:42][CH2:41][CH2:40][CH2:39][O:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][CH3:22])[CH:17]=2)[CH:12]([C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH:11]1[C:32]([O:34][CH3:35])=[O:33]
Reactant: OCCCBr
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1O)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCCO)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
Methyl (1RS,2RS,3RS)-3-(2-Hydroxy-4-methoxy-phenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylate (0.14 g, 0.29 mmol) in dry DMF (1 ml) was added to NaH (9 mg, 0.38 mmol) in a small volume of dry DMF. The mixture was stirred at ambient temperature for 20 min. then 3-bromopropan-1-ol (37 μl, 0.41 mmol) was added. After stirring for 1 h. the product was partitioned between 3 M aqueous HCl and ethyl acetate. The organic layer was washed with water then brine, then dried (MgSO4 anhyd.) filtered and evaporated to give an oil. The product was purified by column chromatography to provide methyl (1RS,2RS,3RS)-3-[2-(3-Hydroxyprop-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.1 g, 65%)(1H-NMR indicated some epimerization had occurred at C-2). This material was used without further purification. Methyl (1RS,2RS,3RS)-3-[2-(3-Hydroxyprop-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylate (0.04 g, 0.075 mmol) was dissolved in methanol (2 ml) and aqueous potassium hydroxide added (2 M, 0.22 ml, 0.44 mmol). The mixture was stirred under reflux overnight then cooled, diluted with water, acidified with 3 M aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water and brine, dried (MgSO4 anhydrous), filtered and evaporated to give an oil. The product was purified by chromatography on silica-gel (eluant: ethyl acetate/hexane/3% acetic acid) to give 12 mg of free acid which was converted to its dicyclohexylamine salt. m.p. 110-112° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].O.Br[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[F:31]>C(COC)OC>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]=[CH:11][CH:10]=2)=[C:25]([F:31])[CH:26]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: Nc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc(N)cc1F
Temperature: 70 °C
Reaction time: 3 h

Procedure:
1.6 g of 1-(t-butoxycarbonyl)pyrrole-2-boronic acid, 200 mg of tetrakistriphenylphosphine palladium, 5 ml of aqueous saturated sodium carbonate solution and 5 ml of water were added in order to a dimethoxyethane (10 ml) solution of 1 g of 4-bromo-3-fluoro-phenylamine, and the reaction liquid was stirred in a nitrogen atmosphere at 70° C. for 3 hours. After cooled, the reaction liquid was filtered through Celite, and the filtrate was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1) to obtain the entitled compound as a pale brown solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12]Br.[CH3:14][Si:15]([CH3:31])([CH3:30])[CH2:16][CH2:17][O:18][CH2:19][N:20]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[CH2:22][C:21]1=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(=O)C>CN(C=O)C>[N+:9]([C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[CH2:2][C:22]1([C:23]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:20]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:30])([CH3:14])[CH3:31])[C:21]1=[O:29])[CH2:12]2)([O-:11])=[O:10]
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 1,2-bis(bromomethyl)-4-nitrobenzene from Step E (40.9 g, 132 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one from Step C (31.5 g, 119 mmol) in DMF (2 L) was added cesium carbonate (129 g, 397 mmol), portionwise, over 5 min. After 18 h, acetic acid (7.6 mL) was added and the mixture was concentrated to a volume of about 500 mL, then partitioned between EtOAc (1.5 L) and H2O (1 L). The organic layer was washed with H2O (1 L), then brine (500 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=412 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1.[I-].[K+].[CH2:26]([NH2:29])[CH:27]=[CH2:28]>O1CCCC1>[CH2:26]([NH:29][CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1)[CH:27]=[CH2:28]
Reactant: ClCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2
Reactant: C=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCNCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 31, 1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide and allylamine in tetrahydrofuran are reacted to give 1-[(allylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: FC1C(NC2C=CC(I)=CC=2F)=C(C(N2CC(C(O)CC3OCCO3)(O)C2)=O)C=CC=1F.C(N(CC)CC)C.[CH:40]([C:43]1[CH:48]=[C:47]([CH:49]([CH3:51])[CH3:50])[CH:46]=[C:45]([CH:52]([CH3:54])[CH3:53])[C:44]=1[S:55](Cl)(=[O:57])=[O:56])([CH3:42])[CH3:41].C([O:62][CH2:63][CH3:64])(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:42][CH:40]([C:43]1[CH:48]=[C:47]([CH:49]([CH3:50])[CH3:51])[CH:46]=[C:45]([CH:52]([CH3:54])[CH3:53])[C:44]=1[S:55]([O:62][CH2:63][CH3:64])(=[O:56])=[O:57])[CH3:41]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: CCOC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(C(O)CC2OCCO2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 35 °C
Reaction time: 3.5 h
Yield: 14 %

Procedure:
1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (148 mg, 0.262 mmol), was dissolved in dichloromethane (10 mL) and treated with 4-(dimethylamino)pyridine (38 mg, 0.31 mmol), triethylamine (0.036 mL, 0.262 mmol) and 2,4,6-triisopropylbenzenesulfonyl chloride (303 mg, 1.0 mmol) at 35° C. for 15 h. 2,4,6-Triisopropylbenzenesulfonyl chloride (100 mg, 0.33 mmol) was added and the mixture was stirred at 35° C. for 3.5 h. The mixture was adsorbed on to silica and purified by column chromatography (silica gel, 40-50% ethyl acetate in hexanes and then 100% ethyl acetate) to give 1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-dioxolan-2-yl)ethyl 2,4,6-tris(1-methylethyl)benzenesulfonate (30 mg, 0.0361 mmol, 14% yield): MS (EI) for C36H42F3IN2O7S: 831 (MH+).
Reaction SMILES: FC1C(F)=CC=CC=1C1C=C[C:12]([O:15]CCCCCCOC(=O)C=C)=[CH:11][CH:10]=1.[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40].BrCCCCCCO>>[C:12]([O:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][Br:27])(=[O:15])[CH:11]=[CH2:10]
Reactant: OCCCCCCCCCCCCBr
Reactant: C=CC(=O)OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Agent: OCCCCCCBr
Product: C=CC(=O)OCCCCCCCCCCCCBr
Yield: 75.1 %

Procedure:
The same procedure as in the synthesis (a) of Example 2 was repeated except that 44.0 g of 12-bromo-1-dodecanol were used instead of 30 g of 6-bromo-1-hexanol to give 39.8 g (Y., 75.1%) of 12-bromododecyl acrylate.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:78][CH:79]1[CH2:84][CH2:83][N:82]([CH3:85])[CH2:81][CH2:80]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:78][CH:79]5[CH2:84][CH2:83][N:82]([CH3:85])[CH2:81][CH2:80]5)=[O:27])=[CH:24][C:23]=4[C:31]([F:33])([F:34])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(C(F)(F)F)c2)CC1
Reaction time: 0.17 h
Yield: 43.5 %

Procedure:
To a mixture of 0.075 g (0.155 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoic acid (I-204) and 8 mL of dimethylformamide was added 0.0313 g (0.232 mmole) of 1-hydroxybenzotriazole, 0.0880 g (0.232 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.080 g (0.617 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.027 g (0.236 mmole) of 4-amino-1-methylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0392 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-3-trifluoromethyl-benzamide (I-205) as a white solid.
Reaction SMILES: N12CCCN=C1CCCCC2.[CH3:12][O:13][C:14](=[O:24])[C:15]#[C:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1.C1(C)C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:38][N+:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[N:40]=1>C(#N)C>[CH3:12][O:13][C:14]([C:15]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[N:38][N:39]2[C:44]=1[CH:43]=[CH:42][C:41]([O:45][CH3:46])=[N:40]2)=[O:24]
Reactant: COC(=O)C#Cc1cccc(F)c1
Reactant: COc1ccc[n+](N)n1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)c1c(-c2cccc(F)c2)nn2nc(OC)ccc12
Reaction time: 1 h
Yield: 53.2 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (5 ml) was added to a stirred, chilled, mixture of (3-fluoro-phenyl)-propynoic acid methyl ester (2.67 g) and 1-amino-3-methoxy-pyridazin-1-ium mesitylene sulphonate (4.89 g) in acetonitrile (80 ml) and the mixture was stirred at 0° for 1 hour then at ambient temperature for 18 hours. The mixture was concentrated in vacuo, and partitioned between ethyl acetate (150 ml) and water (150 ml). The aqueous phase was separated and further extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with water (2×50 ml), brine (25 ml), dried (MgSO4), filtered and evaporated in vacuo to give a solid which was triturated with anhydrous ether:petroleum ether (1:0.5) to give the title compound as a brown solid (2.4 g, 53%).
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH3:10])[CH2:3][C@H:4]1[CH2:8][O:7]C(=O)[NH:5]1.[OH-].[Ba+2].[OH-].C(O)C.C(=O)=O>O>[NH2:5][C@@H:4]([CH2:3][C:2]([CH3:11])([OH:1])[CH3:10])[CH2:8][OH:7]
Reactant: CC(C)(O)C[C@H]1COC(=O)N1
Agent: O=C=O
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(O)C[C@H](N)CO
Reaction time: 8 h
Yield: 83.7 %

Procedure:
A mixture of (4S)-4-(2-hydroxy-2-methylpropyl)-1,3-oxazolidin-2-one (1.0 g, 6.28 mmol), barium hydroxide (3.2 g, 18.8 mmol), ethanol (50 mL) and water (50 mL) was heated to reflux for 4 hours. See Gauthier et al., 2008, Bioorg. Med. Chem. Lett., 18:923-928. After cooling, dry ice (5.5 g, 125.6 mmol) was added and the mixture was stirred vigorously overnight. The suspension was then filtered over CELITE®, rinsing with ethanol. The filtrate was diluted with toluene and evaporated to dryness, yielding crude (S)-2-amino-4-methylpentane-1,4-diol (0.7 g) which was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([O:28][CH2:29][CH2:30][OH:31])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:32])[CH2:10][CH2:9]1)[CH3:7].[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([O:28][CH2:29][CH2:30][O:31][S:40]([C:37]4[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=4)(=[O:42])=[O:41])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:32])[CH2:10][CH2:9]1)[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](OCCO)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](OCCOS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 8 h

Procedure:
The compound of Example 1B (1.50 g, 3.2 mmol) was dissolved in 15 ml of chloroform and 15 ml of pyridine; p-toluenesulfonyl chloride (920 mg, 4.83 mmol) was added, and the mixture was stirred overnight. Chloroform (250 ml) was added, the resultant solution was washed with 5% HCl solution and sat. Na2SO4. After solvent removal in vacuo, the crude product was purified by column chromatography on silica gel (40%—>60% ethyl acetate/hexanes. The yield of the title compound was 1.40 g (71%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]3([OH:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[N:6][CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>O1CCCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[S:12][C:11]([C:13]3([OH:19])[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1)=[O:33]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(-c2cnc(C3(O)CCOCC3)s2)nc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2cnc(C3(O)CCOCC3)s2)nc1)Nc1cc(C(F)(F)F)ccc1F
Reaction time: 1 h

Procedure:
To a solution of Example 7B (0.042 mg, 0.151 mmol) in tetrahydrofuran (1 mL) was added 2-fluoro-5-trifluoromethylphenyl isocyanate (0.022 mL, 0.151 mmol). After 1 h, the mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (preparative reversed-phase high pressure liquid chromatography) using a Zorbax SB-C18 7M 21.2×250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min) to provide the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.68 (br d, J=12.9 Hz, 2 H), 2.07-2.17 (m, 2 H), 3.68-3.80 (m, 4 H), 6.15 (s, 1 H), 7.40-7.45 (m, 1 H), 7.52 (m, 1 H), 7.89 (m, 1 H), 8.08 (m, 1 H), 8.25 (s, 1 H), 8.55-8.60 (m, 2 H), 9.10 (s, 1 H), 9.40 (s, 1 H); MS (ESI) m/z 483 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([N:13]([CH2:15][CH:16]=C)[CH3:14])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClCCl.[O:21]=[O+][O-]>CO>[C:1]([C:5]1[O:9][N:8]=[C:7]([N:10]2[CH:16]([OH:21])[CH2:15][N:13]([CH3:14])[C:11]2=[O:12])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCN(C)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: CN1CC(O)N(c2cc(C(C)(C)C)on2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2.96 g. portion of 1-(5-t-butylisoxazol-3-yl)-3-allyl-3-methylurea was dissolved in 25 ml. of 1:1 by volume dichloromethane:methanol, and the solution was cooled to -78°. Ozone diluted in dry air was bubbled into the solution with good stirring for 30 minutes, after which tlc analysis indicated that the starting material was gone. Nitrogen was bubbled through the mixture for 10 minutes to remove residual dissolved ozone, and then 1 ml. of dimethyl sulfide was added and the mixture was allowed to warm to ambient temperature with continual stirring. The reaction mixture was then diluted with water, the layers were separated, and the product was isolated from the organic layer substantially as shown in Example 2 above to obtain 2.6 g. of the desired product, m.p. 168°-174°. The nuclear magnetic resonance analysis of the product indicated that it was substantially identical to that of Example 1 above.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[C:18]([OH:26])(=[O:25])[C:19]([CH2:21][C:22](O)=[O:23])=[CH2:20]>>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[CH2:21][CH:19]([C:18]([OH:26])=[O:25])[CH2:20]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(F)c1
Reactant: C=C(CC(=O)O)C(=O)O
Product: O=C(O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)c(F)c2)C1

Procedure:
The title compound is prepared in analogy to Example 1a) from 3-fluoro-4-(3-fluoro-benzyloxy)-phenylamine and itaconic acid. Yield: 86% of a colorless solid. MS: m/e=346.1 (M−H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:26]=[CH:27][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:29][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:44](Cl)(=[O:46])[CH3:45]>CN(C)C=O>[C:44]([NH:33][S:30]([C:28]1[CH:27]=[CH:26][C:18]2[N:19]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:14][CH:13]=3)=[N:16][C:17]=2[CH:29]=1)(=[O:32])=[O:31])(=[O:46])[CH3:45]
Reactant: CC(=O)Cl
Reactant: NS(=O)(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(=O)NS(=O)(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23.8 %

Procedure:
A solution of intermediate 69 (0.023 g, 0.05 mmol) in N,N-dimethylformamide (0.200 mL) and lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran) (0.050 ml, 0.05 mmol) was cooled to 0° C. Acetyl chloride (0.005 ml, 0.06 mmol) was added. The reaction mixture was stirred at rt for 1.5 h. At this time, more lithium bis(trimethylsilyl)amide solution (0.050 ml, 0.05 mmol) and acetyl chloride (0.010 ml, 0.014 mmol) were added. The reaction was stirred at rt overnight and concentrated. The crude material was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford the product as a white solid (0.006 g, 18%). 1H NMR (CDCl3) δ 8.52 (br s, 1H), 8.15 (br s, 1H), 7.84 (br m, 1H), 7.61 (br m, 2H), 7.47-7.29 (br m, 5H), 7.22 (br m, 2H), 5.18 (s, 2H), 4.46 (m, 1H), 2.30 (br m, 4H), 2.01 (br m, 2H), 1.82 (br m, 1H), 1.37 (br m, 3H); ESI-MS m/e 504.1 (M+1); HPLC purity (ELSD) 100%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].Cl.[NH2:35][CH:36]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:11]1([N:10]2[C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:33]=[CH:32][C:7]=3[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:28])[NH:35][CH:36]4[CH2:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH2:37]4)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:19])=[O:20])[C:9]2=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: NC1Cc2ccccc2C1
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC2Cc3ccccc3C2)cc1OC
Yield: 70.4 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 100 starting from 0.8 g of the compound obtained in EXAMPLE 13, 0.35 g of 2-aminoindane hydrochloride, 0.8 g of BOP, 2 ml of DIPEA and 20 ml of DCM. It is chromatographed on silica using a DCM/AcOEt mixture (96/4; v/v) as the eluent to give 0.7 g of the expected product in the form of white crystals. M.p.=160° C.
Reaction SMILES: Br[C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[O:18]1[CH2:19][CH2:20][N:15]([C:2]2[NH:11][C:10]3[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=3[N:3]=2)[CH2:16][CH2:17]1
Reactant: Cn1c(=O)c2[nH]c(Br)nc2n(C)c1=O
Reactant: C1COCCN1
Product: Cn1c(=O)c2[nH]c(N3CCOCC3)nc2n(C)c1=O
Yield: 80 %

Procedure:
0.3 moles of the 8-bromo-theophylline, prepared as in the previous paragraph, is refluxed in 1.5 moles of morpholine for two hours. The precipitate obtained is filtered, to give approximately 80% yield of 8-morpholino-theophylline.