Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[CH3:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[C:11]3[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[N:15][CH:14]=[N:13][C:12]=3[O:16][C:17]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3)c(-c3ccc(C)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 30 mg (0.07 mmol) 6-{[5-(4-methylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}-hexanoic acid methyl ester in 0.1 ml methanol, 0.05 ml THF and one drop of water, and add 0.1 ml of 2.5 M sodium hydroxide solution. Stir the mixture for 1 h at RT and then lightly acidify with 1 N hydrochloric acid. Filter off the precipitate with suction, wash several times with water, and dry at high vacuum. 28 mg (96.5% of theor.) of the target compound is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:15]=[C:14]([CH:16]=[CH2:17])[O:13][N:12]=2)=[CH:3]1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>C(O)C.ClCCl>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:15]=[C:14]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[O:13][N:12]=2)=[CH:3]1
Reactant: C=Cc1nc(-c2cn(C)c3ccccc23)no1
Reactant: C1CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: ClCCl
Product: Cn1cc(-c2noc(CCN3CCCCC3)n2)c2ccccc21
Reaction time: 0.17 h

Procedure:
2[3-(1-Methylindol-3-yl)-1,2,4-oxadiazol-5-yl] ethene (0.4 g) was partially dissolved in ethanol. piperidine (2 ml) was added to the mixture and this was stirred for 10 minutes. Ethanol was evaporated under reduced pressure and excess piperidine was removed by heating under high vacuum. The residual oil crystallised upon refrigeration. The crude oil was converted to the monooxalate salt by treatment with 1 equivalent of oxalic acid in dichloromethane which afforded a white amorphous powder. This was recrystallised from ethanol yielding the title compound m.p. 186°-188° C. Found: C, 59.85; H, 6.10; N, 13.95; C18H22N4O.(COOH)2 requires C, 59.99; H, 6.04; N, 13.99%; δH (360 MHz, D2O) 1.48-2.06 (8 H, m, CH2 pip: NCH2CH2 ×2+NCH2CH2CH2), 3.00-3.08 (2 H, m, NCH2) 3.50 (2 H, t, J=9 Hz, CH2CH2N, 3.58-3.70 (4 H, m, CH2CH2N+NCH2CH2 pip, overlapping), 3.87 (3 H, s, NCH3), 7.36 (dt, 1 H, J=7.2, 1.1 Hz, H-5 or H-6), 7.42 (1 H, d, J=7.2, 1.1 Hz, H-5 or H-6) 7.58 (1 H, d, J=8.2 Hz, H-7), 7.89 (s, 1 H, H-2), 8.00 (1 H, d, J=7.5 Hz, H-4); m/z (CI+) 311 (M+ +1, 100%), 226 (30), 157 (70), 98 (90).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH2:11])=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(C2OCCO2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(C2OCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[1,3]Dioxolan-2-yl-benzonitrile described in Preparation Example 119 (3.78 g, 21.6 mmol) was dissolved in tetrahydrofuran (76 mL), lithium aluminum hydride (4.09 g, 108 mmol) was added at 0° C., and the solution was stirred overnight at room temperature. Water (4.09 mL), an aqueous solution of 5N sodium hydroxide (4.09 mL) and water (12.3 mL) were sequentially added to the reaction solution. The reaction solution was filtered through Celite pad, then, the filtrate was evaporated in vacuo, and the title compound (3.92 g, quantitatively) was obtained as a pale yellow oil.
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[OH:7][CH:8]([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[OH-].[Na+]>O1CCCC1.O>[NH2:1][N:13]1[CH2:14][CH2:15][N:10]([CH2:9][CH:8]([OH:7])[CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:11][CH2:12]1
Reactant: NOS(=O)(=O)O
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCC(O)CN1CCN(N)CC1

Procedure:
A solution of hydroxylamine-O-sulfonic acid (0.17 g, 1.5 mmol) in 1:1 tetrahydrofuran-water (10 mL) is added dropwise to a mixture of 1-[2'-hydroxy-3'-octadecyloxypropyl]-piperazine (3.0 g, 7.3 mmol) and sodium hydroxide (0.29 g) in 1:1 tetrahydrofuran-water (30 mL) at 15° C. over a 30 minute period under a nitrogen atmosphere. The resultant mixture is stirred at 15° C. for 2 hours. Three additional portions of NaOH (0.29 g each) are then added to the mixture. The reaction mixture is extracted with dichloromethane, dried over NaOH, concentrated and chromatographed to afford 1-N-Amino-4-N-[2'-hydroxy-3'-octadecyloxypropyl]-piperazine.
Reaction SMILES: [O:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CC([O-])=O.[Na+].C([BH3-])#N.[Na+]>C1COCC1.CO>[CH:15]1([NH:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N[C@H]1CC[C@H](Oc2ccccc2)CC1
Reactant: O=C1CCCCC1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc(O[C@H]2CC[C@H](NC3CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of trans-4-phenoxycyclohexylamine (1 mmol) in 6 ml of THF and 6 ml of MeOH was added cyclohexanone (2 mmol), NaOAc (2 mmol) and 3 g of 3 Å molecular sieves. The mixture is stirred for 10 min after which 1N sodiumcyanoborohydride in tetrahydrofuran (2.4 mmol) is added. The reaction is stirred 1 day at room temperature then filtered through celite washing through with 30 mL of dichloromethane. The organic phase is washed with 10 ml of water, 10 mL of brine, dried (MgSO4), filtered and concentrated in vacuo to give crude cyclohexyl-(trans-4-phenoxy-cyclohexyl)amine which was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[N-:13]=[N+:14]=[N-:15].[Na+]>CCO.O>[N:13]([CH2:2][CH2:3][CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])=[N+:14]=[N-:15]
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(CCCN=[N+]=[N-])OCC

Procedure:
To a solution of diethyl 3-bromopropylphosphonate (1 eq) in EtOH (2 M) was added sodium azide (5 eq) in water (4 M). The reaction mixture was heated at reflux overnight. The mixture was then diluted with water, extracted with DCM three times. The combined organic layers are washed with brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 80-100% EtOAc/Hex to give the product as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][CH2:17][CH2:18][NH:19][C:20](=O)[CH3:21])[C:6]=2[CH:23]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].[OH-].[Na+]>CCOCC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH3:21])[C:6]=2[CH:23]=1
Reactant: CC(=O)NCCCC1c2ccccc2C=Cc2ccc(Cl)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCNCCCC1c2ccccc2C=Cc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Chloro-5-(3-acetamidopropyl)-5H-dibenzo[a,d]cycloheptene is dissolved in absolute ether. The solution is added dropwise to a stirred solution of lithium aluminum hydride in ether, containing 1.25 molar equivalents of the hydride. The mixture is stirred for 2 hours at room temperature, then for 15 hours at reflux. The mixture then is cooled and stirred while water is added cautiously followed by sodium hydroxide solution. The ether layer is separated, washed with water and dried over sodium sulfate. The product is obtained by evaporation of the ether and purified by vacuum distillation.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:15][Cl:16])[CH2:10][C:11](OC)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.CO>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([CH2:15][Cl:16])[CH2:10][CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)C[C@H](CCl)O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CCl)CC=O
Temperature: -78 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
To a solution of (R)-methyl 3-(tert-butyldimethylsilyloxy)-4-chlorobutanoate (27.9 g, 104.7 mmol) in CH2Cl2 was added dropwise DIBAL-H (120 mL, 1 M in toluene, 120 mmol) at −78° C. under N2 atmosphere. The mixture was stirred at −78° C. for 4 h. CH3OH (80 mL) was added slowly to the reaction mixture at −78° C. Then the temperature was warmed to room temperature gradually. The mixture was filtered and the cake was washed with CH2Cl2. The combined filtrates were concentrated under reduced pressure and purified by column chromatography (PE) to give (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (13 g, 60% over 2 steps). 1H NMR (300 MHz, CDCl3) δ 9.80 (t, J=1.6 Hz, 1H), 4.35-4.42 (m, 1H), 3.53 (dd, J=11.1 Hz, 4.8 Hz, 1H), 3.46 (dd, J=12 Hz, 6.3 Hz, 1H), 2.63-2.82 (m, 2H), 0.87 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13]([OH:15])=O)[CH2:10][NH:9][C:8]=2[CH:16]=1.[C:19](=[O:36])([O:34][CH3:35])[O:20][C:21]1[CH:26]=[C:25]([NH2:27])[C:24]([Br:28])=[CH:23][C:22]=1[CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.N1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1CCCO1>[C:19](=[O:36])([O:34][CH3:35])[O:20][C:21]1[CH:26]=[C:25]([NH:27][C:13]([CH:11]2[O:12][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:18])[F:17])=[CH:16][C:8]=3[NH:9][CH2:10]2)=[O:15])[C:24]([Br:28])=[CH:23][C:22]=1[CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(O)C1CNc2cc(OC(F)(F)F)ccc2O1
Reactant: COC(=O)Oc1cc(N)c(Br)cc1C1CCCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: CC1CCCO1
Product: COC(=O)Oc1cc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(Br)cc1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
6-(Trifluoromethoxy)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (490 mg, 1.86 mmol) and (5-amino-4-bromo-2-cyclopentyl-phenyl) methyl carbonate (585 mg, 1.86 mmol) were dissolved in 2-methyltetrahydrofuran (13 mL). Pyridine (376 μL, 4.65 mmol) and T3P (2960 mg, 2.8 mL of 50% w/w solution, 4.66 mmol) were added and the reaction was stirred for 1 h at room temperature. Purification by silica gel chromatography (10-75% ethyl acetate/hexanes) yielded 4-bromo-2-cyclopentyl-5-(6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)phenyl methyl carbonate (802 mg, 77% yield). LC/MS m/z 560.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:12])=[C:4]([F:13])[CH:3]=1.C1COCC1.[BH4-].[Na+]>CCO>[Br:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:12])=[C:4]([F:13])[CH:3]=1
Reactant: O=C1CCc2c(F)cc(Br)c(F)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OC1CCc2c(F)cc(Br)c(F)c21

Procedure:
To a mixture of 6-bromo-4,7-difluoro-2,3-dihydro-1H-inden-1-one (0.5 g), THF (1 mL) and EtOH (1 mL) was added NaBH4 (100 mg). After 1 hour the reaction mixture was concentrated and the residue distributed between water and EA. The organic phase was washed with water (3 times), dried (Na2SO4), filtered and concentrated. The residue was purified by preparative HPLC to provide the subtitle compound. MS ESI+: m/z=249 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[C:16](=[O:31])[C:17]4[CH:22]=[N:21][N:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]#[N:27])[C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.Cl.C(=O)([O-])[O-].[NH4+:44].[NH4+]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]([C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=4)[C:16](=[O:31])[C:17]4[CH:22]=[N:21][N:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]([NH2:44])=[NH:27])[C:18]=4[N:19]=3)=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: N#Cc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)cn5)cc4)nc32)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: N=C(N)c1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)cn5)cc4)nc32)c1

Procedure:
At 0° C., 3-[6-[4-(5-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzonitrile (prepared as described in example 27, 0.30 g, 0.58 mmol) is added to methanol saturated with hydrogen chloride gas (7 mL) with stirring. The reaction mixture is allowed to reach rt and stirred there for 30 h. The reaction mixture is then concentrated to a dry residue. It is taken in dry methanol (6 mL) and ammonium carbonate (0.548 g, 3.48 mmol) is added. After stirring at rt for 48 h, the reaction mixture is concentrated and the residue obtained is purified by preparative HPLC to afford 3-[6-[4-(5-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzamidine. 1H NMR (DMSO-d6, 400 MHz) δ 9.40 (br, 4H), 8.62 (m, 2H), 8.53 (s, 1H), 8.32 (s, 1H), 8.0 (d, 1H), 7.83 (m, 4H), 7.64 (d, 1H), 7.43 (m, 5H), 6.96 (d, 1H), 5.6 (br, 1H); LC-MS calculated for C29H21ClN8O (M+H+) 533.2, found 533.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH3:35][N:36]([CH3:44])[C:37]([N:39]([CH3:43])[CH2:40][C:41]#[CH:42])=[O:38].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:42]#[C:41][CH2:40][N:39]([CH3:43])[C:37]([N:36]([CH3:44])[CH3:35])=[O:38])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: C#CCN(C)C(=O)N(C)C
Reactant: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COc1cc2c(Nc3c(Cl)cc(C#CCN(C)C(=O)N(C)C)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Reaction time: 3 h
Yield: 68.6 %

Procedure:
This was prepared using the method described in example 26 but it was carried out at room temperature over 3 hr using N-(5-chloro-7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4ylpropoxy)quinazolin-4-amine (310 mg, 0.52 mmol), N,N,N′-trimethyl-N′-prop-2-yn-1-ylurea (145 mg, 1.04 mmol), bis(triphenylphosphine) palladium(II) dichloride (36 mg, 10 mol %), copper(I) iodide (10 mg, 10 mol %) and diisopropylamine (105 mg, 1.04 mmol) in ethyl acetate (10 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent to give the title compound (218 mg, 69%) as a pale brown solid; NMR Spectrum:(CDCl3) 2;11 (quintet, 2H), 2.48 (m, 4H), 2.56 (t, 2H), 2.87 (s, 6H), 2.92 (s, 3H), 3.72 (m, 4H), 4.00 (s, 3H), 4.15 (s, 2H), 4.25 (t, 2H), 6.06 (s, 2H), 7.03 (s, 1H), 7.10-7.30 (s(broad), 1H), 7.20 (s, 1H), 7.31 (s, 1H), 8.60 (s, 1H); Mass Spectrum: M+H+ 611/613.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH3:30])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:17](Br)[C:11]=2[N:10]([CH3:31])[C:9]1=[O:32])(=[O:3])[CH3:2].[CH3:33][Sn](C)(C)C>CN(C=O)C.CC(=O)OCC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH3:30])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:17]([CH3:33])[C:11]=2[N:10]([CH3:31])[C:9]1=[O:32])(=[O:3])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CC(=O)OCCCn1c(=O)c2c(c(Br)c(-c3cccc(OC(F)(F)F)c3)n2C)n(C)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCCCn1c(=O)c2c(c(C)c(-c3cccc(OC(F)(F)F)c3)n2C)n(C)c1=O
Temperature: 25 °C
Yield: 88.2 %

Procedure:
To a solution of 3-(7-bromo-1,5-dimethyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (25 mg, 0.05 mmol) in DMF (1 mL) was added tetramethylstannane (26.7 mg, 0.15 mmol) and Pd(PPh3)2Cl2 (5 mg). The reaction was heated at 120° C. (MW) for 45 min, cooled to RT then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give 3-(1,5,7-trimethyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (20 mg, 91.8% yield) as an oil. LCMS: MH+ 454 and TR=1.625 min. Used without further purification.
Reaction SMILES: [CH3:1][S:2]([N:5]=[C:6]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)OC1C=CC=CC=1)(=[O:4])=[O:3].[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>C(#N)C>[Br:21][C:22]1[CH:23]=[C:24]([NH:25][C:6](=[N:5][S:2]([CH3:1])(=[O:3])=[O:4])[O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)N=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1cccc(Br)c1
Solvent: CC#N
Product: CS(=O)(=O)N=C(Nc1cccc(Br)c1)Oc1ccccc1
Temperature: 70 °C
Yield: 52.1 %

Procedure:
Diphenyl methylsulfonylcarbonimidate from step A (0.75 g, 2.59 mmol) and 3-bromoaniline (0.28 ml, 2.59 mmol) were dissolved in acetonitrile (5 ml) and heated to 70° C. for 12 hours. The reaction was cooled to room temperature and concentrated under vacuum. Purification by flash chromatography (30% EtOAc/hexanes) afforded phenyl N-3-bromophenyl-N′-(methylsulfonyl)carbamimidate (0.50 g, 1.35 mmol, 52%).
Reaction SMILES: Br[C:2]1[C:3]([Cl:13])=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[C:14]1(/[CH:20]=[CH:21]/B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])O.[K+]>O1CCOCC1.O.C(OCC)(=O)C>[Cl:13][C:3]1[C:2](/[CH:21]=[CH:20]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][C:10]2[NH:9][C:8](=[O:12])[CH2:7][O:6][C:5]=2[CH:4]=1
Reactant: O=C1COc2cc(Cl)c(Br)nc2N1
Reactant: OB(O)/C=C/c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1COc2cc(Cl)c(/C=C/c3ccccc3)nc2N1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
6-Bromo-7-chloro-4H-pyrido[3,2-b][1,4]oxazin-3-one (15a) (22 g, 83.7 mmole) and trans-2-phenylvinylboronic acid (17.33 g, 117 mmole) were dissolved in 1,4-dioxane (300 mL) and the solution was degassed with argon. (Ph3P)4Pd (1.9 g, 2 mole %) was added, followed by a solution of potassium hydrogen carbonate (21 g, 210 mmole) in H2O (100 mL). The reaction was heated at reflux under argon overnight, then was cooled to room temperature and diluted with ethyl acetate (1 L). The solution was washed sequentially with H2O and brine, dried (Na2SO4), and concentrated in vacuo. The residue was slurried with chloroform (120 mL), then diluted with diethyl ether (100 mL). The precipitated product was collected by filtration and washed with ether to provide the product (16.4 g, 68%) as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([N:16]=[C:17]=[O:18])(=[O:15])[C:12]([CH3:14])=[CH2:13]>C(OCC)C>[C:11]([NH:16][C:17]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:18])(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: C=C(C)C(=O)N=C=O
Solvent: CCOCC
Product: C=C(C)C(=O)NC(=O)Nc1ccc([N+](=O)[O-])cc1
Yield: 79 %

Procedure:
Into 500 ml of a diethyl ether solution of 13.8 g (0.1 mol) of p-nitroaniline was added dropwise 50 ml of a diethyl ether solution of 11.1 g (0.1 mol) of methacryloyl isocyanate over about 30 minutes in an ice bath. After completion of the addition, the produced crystal was filtered and the filtrate was distilled under a reduced pressure. The yellow solid gathered from the filtration and the distillation residue was recrystallized with methyl ethyl ketone to obtain 19.7 g of 1-methacryloyl-3-(4-nitrophenyl)urea (Compound 1) which had a decomposing point of 241° to 244° C. and was yellow needle crystal.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1([C:25](Cl)=[O:26])[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2>>[CH:1]1([NH:6][C:25]([C:12]2([CH2:11][CH2:10][CH2:9][CH2:8][Br:7])[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NC1CCCC1)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1c from cyclopentylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][NH2:23])[O:19][C:18]4=[O:24])=[CH:13][C:12]=3[F:25])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:26][CH:27]([Cl:31])[C:28](O)=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[O:1]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][NH:23][C:28](=[O:29])[CH:27]([Cl:31])[Cl:26])[O:19][C:18]4=[O:24])=[CH:13][C:12]=3[F:25])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(Cl)Cl
Reactant: NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1)C(Cl)Cl
Yield: 52 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine (0.2 mmol, Example H) with dichloroacetic acid (2.1 mmol), dicyclohexylcarbodimide (2.1 mmol) in dichloromethane (10 ml) at a temperature 0-25° C. for 3 hours followed by silica gel column chromatographic purification in 52% yield.