Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH:5]1([C:9]([OH:11])=O)[CH2:8][CH2:7][CH2:6]1.[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[N+](CC)([O-])=O>[CH:5]1([C:9]([C:15]2[CH:16]=[CH:17][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)=[O:11])[CH2:6][CH2:7][CH2:8]1
Reactant: O=C(O)C1CCC1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: COc1ccc(C(=O)C2CCC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of AlCl3 (13.4 g) in nitroethane (25 ml) was added to a solution of cyclobutane carboxylic acid (10.0 g) and anisole (10.8 g) in nitroethane (75 ml) at 10° C. The mixture was stirred for 5 hours at room temperature, was than poured on ice and extracted with MTBE. The organic phase was washed with aqueous sodium hydroxide, water and brine, dried (MgSO4) and concentrated in vacuo. The essentially clean ketone (10.8 g) was used in the next step.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]([CH:15]([OH:47])[CH2:16][CH:17]([N:21]([CH2:39][O:40][C:41](=[O:46])[CH2:42][CH:43]([CH3:45])[CH3:44])[C:22](=[O:38])[CH:23]([NH:28][C:29]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]2[CH3:37])=[O:30])[CH:24]([CH3:27])[CH2:25][CH3:26])[CH:18]([CH3:20])[CH3:19])[S:13][CH:14]=1)=[O:9])([OH:3])=[O:2].[C:48](OC(=O)C)(=[O:50])[CH3:49].O1CCOCC1.O>N1C=CC=CC=1>[C:48]([O:47][CH:15]([C:12]1[S:13][CH:14]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])[N:11]=1)[CH2:16][CH:17]([N:21]([CH2:39][O:40][C:41](=[O:46])[CH2:42][CH:43]([CH3:45])[CH3:44])[C:22](=[O:38])[CH:23]([NH:28][C:29]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[CH3:37])=[O:30])[CH:24]([CH3:27])[CH2:25][CH3:26])[CH:18]([CH3:20])[CH3:19])(=[O:50])[CH3:49]
Reactant: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(COC(=O)CC(C)C)C(CC(O)c1nc(C(=O)NCCCC(=O)O)cs1)C(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(COC(=O)CC(C)C)C(CC(OC(C)=O)c1nc(C(=O)NCCCC(=O)O)cs1)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.6 %

Procedure:
A 0.10 M solution of 13b (15.0 mg, 0.0220 mmol) in pyridine (0.220 mL) was cooled to 0° C., and acetic anhydride (10.4 μL, 0.110 mmol) was added. The reaction mixture was allowed to warm to rt over 2 h and was stirred at rt for 24 h. The reaction mixture was then cooled to 0° C., and a 1:1 mixture of dioxane/water (0.630 mL) was added. The mixture was allowed to warm to rt and was stirred for 12 h at rt. The solvent was removed under reduced pressure. Column chromatography (100:0 to 90:10 CH2Cl2:MeOH) afforded 13.0 mg (81%) of 3 as an amorphous solid. [α]D23=+24.3 (c=0.7, MeOH). IR: 1371, 1420, 1497, 1544, 1667, 1741, 2342, 2360, 2840, 2872, 2929, 2961, 3293, 3368 cm−1. 1H NMR (500 MHz, MeOD): δ 0.79 (d, 3H, J=6.7 Hz), 0.85 (d, 3H, J=6.9 Hz), 0.87-0.92 (m, 6H), 0.96 (d, 3H, J=6.6 Hz), 1.05 (d, 3H, J=6.3 Hz), 1.15-1.23 (m, 1H), 1.35-1.42 (m, 1H), 1.57-1.65 (m, 3H), 1.69-1.72 (m, 1H), 1.77-1.81 (m, 1H), 1.84-1.93 (m, 4H), 1.95-2.01 (m, 2H), 2.08-2.18 (m, 2H), 2.13 (s, 3H), 2.28-2.39 (m, 4H), 2.33 (s, 3H), 2.48-2.53 (m, 1H), 2.94 (app d, 1H, J=10.1 Hz), 3.08 (app d, 1H, J=11.3 Hz), 3.40-3.43 (m, 2H), 4.41 (br s, 1H), 4.60 (d, 1H, J=9.5 Hz), 5.40 (d, 1H, J=12.4 Hz), 5.87 (d, 1H, J=10.8 Hz), 6.13 (d, 1H, J=10.8 Hz), 8.18 (s, 1H). 13C NMR (125 MHz, MeOD) δ 10.7, 16.4, 20.3, 20.70, 20.76, 22.73, 22.74, 23.7, 25.54, 22.56, 26.7, 26.9, 31.1, 32.2, 34.7, 35.9, 37.4, 40.2, 44.18, 44.25, 55.2, 56.5, 69.7, 70.7, 125.6, 150.8, 163.2, 170.7, 171.9, 173.3, 173.8, 176.4, 180.5. HRMS (FAB) calcd for C35H58N5O9S (M+H): 724.3955. Found: 724.3937.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16].[CH:26]12[CH2:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][C@@H:27]2[NH2:33].C=O.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[CH:26]12[CH2:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][C@@H:27]2[N:33]([CH3:1])[CH2:22][C:21]1[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=1
Reactant: N[C@H]1CC2CCC1C2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(Cc1ccc([N+](=O)[O-])cc1)[C@H]1CC2CCC1C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium triacetoxyborohydride (3.5 mmol, 0.75 g) was added to a mixture of 4-nitro-benzaldehyde Compound 4a (2.8 mmol, 0.42 g), (2S)-bicyclo[2.2.1]hept-2-ylamine Compound 15d (3.0 mmol, 0.33 g) and glacial acetic acid (3 drops) in CH2Cl2 (40 mL). The resulting suspension was allowed to stir at room temperature for 12 hrs. An aliquot of the reaction mixture showed the formation of product (MS m/e 247, 100%). An aqueous solution of formaldehyde (37% solution, 9.6 mmol, 0.8 mL) was added to the reaction mixture followed by sodium triacetoxyborohydride (3.5 mmol, 0.75 g) and the mixture was allowed to stir at r.t. for 2 hrs. The reaction mixture was basified with 2N NaOH solution and was extracted with CH2Cl2. The organic layer was washed with brine, separated and dried over Na2SO4. The drying agent was filtered and the solvent was removed in vacuo to obtain (2S)-bicyclo[2.2.1]hept-2-yl-methyl-(4-nitro-benzyl)-amine Compound 15e (0.72 g, 98%) as an orange oil. MS m/e 261 (M+H, 100%), which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=O.[N+:11]([CH2:14][C:15](OCC)=[O:16])([O-:13])=[O:12].N1CCCCC1>CC1C=CC=CC=1C>[I:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][C:15](=[O:16])[C:14]([N+:11]([O-:13])=[O:12])=[CH:4]2
Reactant: Nc1ccc(I)cc1C=O
Reactant: CCOC(=O)C[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: Cc1ccccc1C
Product: O=c1[nH]c2ccc(I)cc2cc1[N+](=O)[O-]

Procedure:
A stirred mixture of 2-amino-5-iodobenzaldehyde (2.0 g), ethyl nitroacetate (4.2 g), and piperidine (0.7 g) was heated under reflux for 1.5 hours in o-xylene (100 cm3). The cooled solution was then concentrated in vacuo and the solid residue was recrystallised from chloroform-isopropanol to afford 6-iodo-3-nitro-2-(1H)-quinolone, m.p. 279°-282°, (1.14 g).
Reaction SMILES: [F:1][CH:2]([F:36])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[N:17]([N:21]=[C:22]([NH:24][C:25]3[CH:35]=[CH:34][C:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33][C:27]=4[CH:26]=3)[N:23]=2)[CH:18]=[CH:19][CH:20]=1.Cl[CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40]>>[F:36][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[N:17]([N:21]=[C:22]([NH:24][C:25]3[CH:35]=[CH:34][C:28]4[CH2:29][CH2:30][N:31]([CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[CH2:32][CH2:33][C:27]=4[CH:26]=3)[N:23]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(OCC(F)F)c(-c2cccn3nc(Nc4ccc5c(c4)CCNCC5)nc23)c1
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)CN1CCc2ccc(Nc3nc4c(-c5cc(S(C)(=O)=O)ccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
2-(7-{8-[2-(2,2-Difluoro-ethoxy)-5-methanesulfonyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-N,N-dimethyl-acetamide was prepared from {8-[2-(2,2-difluoro-ethoxy)-5-methanesulfonyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7yl)-amine (0.127 g, 0.247 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.038 mL, 0.371 mmol) in a manner analogous to Example 313 to give product (0.060 g, 40%). MP=128-130° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.50 (s, 1H), 8.81 (d, 1H), 8.20 (s, 1H), 8.00 d, 1H), 7.65 (d, 1H), 7.50 (m, 2H), 7.32 (s, 1H), 7.10 (t, 1H), 6.98 (d, 1H), 6.28 (br m, 1H), 4.54 (m, 2H), 3.25 (m, 5H), 3.10 (s, 3H), 2.80 (m, 7H), 2.60 (m, 4H). MS=599 (MH)+.
Reaction SMILES: C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.N1CCC[C@H]1CO.C(N(CC)CC)C.[C:30]([N:37]1[CH2:43][CH2:42][CH2:41][C@H:38]1[CH2:39][OH:40])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>ClCCl>[C:30]([N:37]1[CH2:43][CH2:42][CH2:41][C@H:38]1[CH:39]=[O:40])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: OC[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reaction time: 8 h

Procedure:
A solution of 31.4 g (144 mmol) di-tert-butyl dicarbonate in dichloromethane was added to a solution of 14.6 g (144 mmol) L-prolinol and 22.1 ml (159 mmol) triethyl amine in dichloromethane at 0° C. The reaction was left overnight at rt. The dichloromethane phase was washed with 30% citric acid aq, saturated NaCl aq and saturated NaHCO3 aq. The organic phase was dried with Na2SO4 and evaporated. Yield 27.71 g (138 mmol, 96%). 27.71 g (138 mmol) BOC-L-prolinol was oxidized to the corresponding aldehyde according to procedure G. Yield of crude product 22.63 g. The product was purified with a silica column using 20% ethyl acetate in petroleum ether as eluent. Yield 18.4 g (92 mmol, 67%).
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:19]1(=[O:30])[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]2[CH2:20]1.C1(C)C=CC=CC=1>O1CCCC1>[CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[CH2:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([OH:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Yield: 55 %

Procedure:
A solution of 1.28 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, 0.81 g of homophthalic anhydride, 50 ml of toluene and 25 ml of tetrahydrofuran was heated to reflux for 0.5 hr. The solvents were removed by rotary evaporation and the residual materials were triturated with ethyl ether to yield 1.15 g of (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid. Recrystallization from acetonitrile yielded 0.81 g of material; m.p. 204°-206° C.
Reaction SMILES: [C:1](#[N:3])C.[Br:4][C:5]1[CH:16]=[CH:15][C:8]2[NH:9][C:10](=O)[O:11][C:12](=O)[C:7]=2[CH:6]=1.C[NH:18]C(=N)SC.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:15][CH:16]=1)[NH:9][C:10]([NH:3][CH3:1])=[N:18][C:12]2=[O:11]
Reactant: CNC(=N)SC
Reactant: CC#N
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CNc1nc(=O)c2cc(Br)ccc2[nH]1
Yield: 65 %

Procedure:
To a combined solution of acetonitrile (360 mL) and water (90 mL) was added 6-bromo-1H-benzo[d][1,3]oxazine-2,4-dione (24.2 g, 0.1 mol), 1,2-dimethyl-isothiourea hydriodic (23.2 g, 0.1 mol) followed by anhydrous sodium carbonate (11.7 g, 0.11 mol) and the mixture was heated to reflux for 3 hours. After cooling down, the precipitate was collected by filtration, washed with water to afford 6-bromo-2-methylamino-1H-quinazolin-4-one (16.5 g, 65 mmol, 65%) as a light yellow powder. 1H NMR (DMSO-d6): δ 11.20 (b, 1H), 7.91-7.90 (d, 1H), 7.64-7.63 (d, 1H), 7.20-7.18 (d, 1H), 6.30 (b, 1H), 2.82-2.81 (d, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][O:8][C:5]2=[N:6][CH:7]=1.BrC1C=C2C=CNC2=NC=1.[CH3:21][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:23]([CH2:25][CH:26]=[CH2:27])[CH3:24]>[Pd]>[CH3:21][N:22]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH:23]([CH2:25]/[CH:26]=[CH:27]/[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][O:8][C:5]2=[N:6][CH:7]=1)[CH3:24]
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Reactant: Brc1cnc2occc2c1
Agent: [Pd]
Agent: Brc1cnc2[nH]ccc2c1
Product: CC(C/C=C/c1cnc2occc2c1)N(C)C(=O)OC(C)(C)C

Procedure:
Other polycyclic aromatic compounds of the present invention can be prepared by the Heck reaction. Thus both 5-bromofuro[2,3-b]pyridine and 5-bromo-1H-pyrrolo[2,3-b]pyridine can undergo palladium catalyzed coupling with the previously described olefinic amine side chain, N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine, to give (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-furo[2,3-b]pyridinyl)-4-penten-2-amine and (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-1H1H-pyrrolo[2,3-b]pyridinyl)-4-penten-2-amine respectively. Subsequent removal of the tert-butoxycarbonyl group with trifluoroacetic acid will provide (4E)-N-methyl-5-(5-furo[2,3-b]pyridinyl)-4-penten-2-amine and (4E)-N-methyl-5-(5-1H-pyrrolo[2,3-b]pyridinyl)-4-penten-2-amine. The requisite 5-bromofuro[2,3-b]pyridine and 5-bromo-1H-pyrrolo[2,3-b]pyridine can be made from 2,3-dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2,3-b]pyridine respectively, by bromination (bromine and sodium bicarbonate in methanol) and dehydrogenation (2,3-dichloro-5,6-dicyano-1,4-benzoquinone), using chemistry described by E. C. Taylor et al., Tetrahedron 43: 5145-5158 (1987). 2,3-Dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2,3-b]pyridine are, in turn, made from 2-chloropyrimidine (Aldrich Chemical Company), as described by A. E. Frissen et al., Tetrahedron 45: 803-812 (1989), by nucleophilic displacement of the chloride (with the sodium salt of 3-butyn-1-ol or with 4-amino-1-butyne) and subsequent intramolecular Diels-Alder reaction. Using similar chemistry, 2,3-dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2,3-b]pyridine are also produced from 3-methylthio-1,2,4-triazene (E. C. Taylor et al., Tetrahedron 43: 5145-5158 (1987)), which in turn is made from glyoxal and S-methylthiosemicarbazide (W. Paudler et al., J. Heterocyclic Chem. 7: 767-771 (1970)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[C:18]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[N:19]=2)[C:14](O)=[O:15])[CH3:9])=[CH:4][CH:3]=1.[NH3:27].CO>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[C:18]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[N:19]=2)[C:14]([NH2:27])=[O:15])[CH3:9])=[CH:4][CH:3]=1
Reactant: N
Reactant: C[C@H](Nc1cc(C(=O)O)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Solvent: CO
Product: C[C@H](Nc1cc(C(N)=O)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To 500 mg of (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)_isonicotinatic acid (Example 141), was added 15 ml of 7N ammonia/methanol solution and the mixture was stirred at 100° C. for 3 days in a sealed tube. The solvent of the reaction solution was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 310 mg of the objective compound as pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:11][NH2:12].C(OCC)(=O)C>C(O)C>[NH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:9]=2)[NH:12][N:11]=1
Reactant: N#Cc1cc(Br)ccc1F
Reactant: NN
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1n[nH]c2ccc(Br)cc12
Temperature: 140 °C
Yield: 96.5 %

Procedure:
To a solution of 5-bromo-2-fluorobenzonitrile (0.40 g, 2.0 mmol.) in ethanol (3 mL) was added hydrazine (0.64 g, 20 mmol.). The reaction mixture was heated in a microwave reactor at 140° C. for 20 minutes. Ethyl acetate (100 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to yield 3-amino-5-bromoindazole 165 (0.41 g, 1.93 mmol.). The crude product was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8].[CH3:12][S:13][CH2:14][CH2:15]Cl>CN(C=O)C>[CH3:12][S:13][CH2:14][CH2:15][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8]
Reactant: CSCCCl
Reactant: O=Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
NaH (1.3 g, 54 mmol) is added to a solution of 5.0 g (41 mmol) 3-hydroxybenzaldehyde in 30 ml DMF at 0° C. After stirring for 1 h 4.44 ml (45 mmol) 2-chloroethyl methyl sulphide is added. The reaction mixture is warmed to room temperature and stirring is continued for 16 h. Then the reaction mixture is poured onto water and extracted with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane/EtOAc=3:1) to afford the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[O:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH2:17]([O:16][C:14]([C:13]([OH:12])([CH2:10][C:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=1)=[O:11])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])[CH3:18]
Reactant: CC(=O)c1ccc(C)c(F)c1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Product: CCOC(=O)C(O)(CC(=O)c1ccc(C)c(F)c1)C(=O)OCC
Temperature: 120 °C
Reaction time: 48 h
Yield: 79.8 %

Procedure:
A mixture of 3′-fluoro-4′-methylacetophenone (4.92 g, 32.3 mmol) and diethyl ketomalonate (6.19 g, 35.6 mmol) was stirred at 120° C. for 48 hours. The temperature of the reaction mixture was allowed to drop back to room temperature, and the mixture was purified by column chromatography on silica gel [silica gel 100 g, chloroform/ethyl acetate (10/1)] to yield the title compound as yellow crystals (8.41 g, 79.3%).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][N:12]=2)=[CH:7][C:6]=1[CH3:21].Cl>C1COCC1.CCOC(C)=O>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][N:12]=2)=[CH:7][C:6]=1[CH3:21]
Reactant: CCOC(=O)c1cc(-c2ccc(OCOC)c(C)c2)no1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(O)c(C)c2)no1
Yield: 70.5 %

Procedure:
A solution of ethyl 3-[4-(methoxymethoxy)-3-methylphenyl]-5-isoxazolecarboxylate (725 mg, 2.49 mmol) and aqueous 4 N HCl solution (6 mL) in THF (10 mL) was stirred at 25° C. for 16 h. The reaction mixture was diluted with EtOAc and successively washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (434 mg, 70% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:29][C:30]([CH:33]=O)([CH3:32])[CH3:31]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][N:20]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1
Reactant: CC(C)(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(CC(C)(C)C)C3)cc1

Procedure:
Method as described for example 26 using (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 7) and pivaldehyde as starting materials. Purified by prep HPLC (low pH).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:32])[C:4](=[O:31])[C:5]([CH3:30])([CH3:29])[C@:6]([C:9]2[CH:10]=[C:11]([NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][C:18]=3[O:27][CH3:28])[CH:12]=[CH:13][C:14]=2[F:15])([CH3:8])[N:7]=1.[Li+].[OH-]>C1COCC1.CO.O>[NH2:1][C:2]1[N:3]([CH3:32])[C:4](=[O:31])[C:5]([CH3:29])([CH3:30])[C@:6]([C:9]2[CH:10]=[C:11]([NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=3[O:27][CH3:28])[CH:12]=[CH:13][C:14]=2[F:15])([CH3:8])[N:7]=1
Reactant: COC(=O)c1ccc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-methyl 4-(3-(2-amino-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydropyrimidin-4-yl)-4-fluorophenylamino)-3-methoxybenzoate (example 123, 0.05 mmol) in THF (1 ml), MeOH (0.3 ml) and H2O (0.3 ml) was added LiOH (1N, 0.1 mmole) and the reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated in vacuo, the residue was dissolved in aqueous HCl (0.5N) until pH=5 and extracted with dichloromethane. The organic phase was separated, dried over Na2SO4 and evaporated to yield a white solid. The solid material was triturated with Et2O, filtered and dried to yield the title compound as a white solid. MS (ESI): m/z=429.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]([CH3:27])[CH3:26])[CH:19]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]([CH3:27])[CH3:26])[CH:19]=2)=[CH:3][C:2]([C:33]2[CH:34]=[C:29]([Cl:28])[C:30]([OH:45])=[C:31]([Cl:44])[CH:32]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)Cc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)c1
Product: CN(C)Cc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)c1
Yield: 74.7 %

Procedure:
Following general procedure D, (6-bromo-4-(3-((dimethylamino)methyl)phenylamino)quinoline-3-yl)(cyclopropyl)methanone (100 mg, 0.23 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (98 mg, 0.34 mmol) to afford the desired product (87 mg, 75%) as a yellow-green solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.45 (s, 1H), 8.25 (dd, J=8.8, 1.9 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.97 (s, 1H), 7.74 (m, 1H), 7.63 (m, 3H), 7.28 (s, 2H), 4.39 (s, 2H), 2.84 (m, 7H), 1.19 (m, 4H); ESI MS m/z 506 [C28H25Cl2N3O2+H]+; HPLC 98.0% (AUC), tR=11.15 min.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[NH2:13][C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=1[CH2:29][CH2:30][CH3:31].[C:35]([O:46][CH3:47])(=[O:45])[C:36]1[CH:44]=[CH:43][CH:42]=[C:38]([C:39](O)=[O:40])[CH:37]=1.C(N(CC)CC)C>ClCCl>[CH3:47][O:46][C:35](=[O:45])[C:36]1[CH:44]=[CH:43][CH:42]=[C:38]([C:39]([NH:13][C:14]2[CH:34]=[CH:33][CH:32]=[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[CH2:29][CH2:30][CH3:31])[CH:15]=2)=[O:40])[CH:37]=1
Reactant: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(OCc2cccc(NC(=O)c3cccc(C(=O)OC)c3)c2)ccc(C(C)=O)c1O
Reaction time: 5 h
Yield: 77.1 %

Procedure:
Add ethyldimethylaminopropylcarbodiimide hydrochloride (2.47 g, 12.9 mmol) to a solution of 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (1.54 g, 5.14 mmol) and methyl hydrogen isophthalate (1.11 g, 6.17 mmol) in dichloromethane (40 mL) at 0° C. Add triethylamine (3.59 mL, 25.7 mmol) and stir at room temperature for 72 hours. At 5 hours, add additional methyl hydrogen isophthalate (200 mg). Stir overnight. Wash the mixture twice with 2N hydrochloric acid, saturated sodium bicarbonate, brine, dry, and concentrate. Triturate the residue with 1:1 hexanes: dichloromethane, and filter to afford the title compound as an off-white powder (1.83 g, 77%): 1H NMR (CDCl3) δ 0.97 (t, 3H), 1.59 (sextet, 2H), 2.56 (s, 3H), 2.72 (t, 2H), 3.98 (s, 3H), 5.20 (s, 2H), 6.49 (d, 1H), 7.25 (m, 1H), 7.42 (t, 1H), 7.56-7.64 (m, 3H), 7.79 (s, 1H), 7.89 (s, 1H), 8.15 (d, 1H), 8.24 (d, 1H), 8.48 (s, 1H), 12.75 (s, 1H).