Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([C:8]([OH:10])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([C:8]([C:20]2[CH:21]=[CH:22][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Br)sc1Cl
Reactant: COc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(Br)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To a solution of acid 1 (2.0 g, 8.28 mmol) in CH2Cl2 (50 mL) were added oxalyl chloride (0.87 mL, 9.94 mmol) and catalytic amounts of DMF at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was evaporated in vacuo and dried under high vacuum. The crude acid chloride was dissolved with CH2Cl2 (30 mL) and cooled to 0° C. To the mixture was added anisole (0.9 mL, 8.28 mmol) at 0° C. and stirred at 0° C. for 5 min. To the reaction mixture was added AlCl3 (1.2 g, 8.28 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 30 min, warmed up to room temperature and stirred at room temperature for 15 hours. The mixture was poured into ice-water and extracted with CH2Cl2 (50 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the title compound 2 (2.68 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[I:11]I>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([I:11])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1ccc(F)c(Cl)c1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1cc(Cl)c(F)cc1I
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To a solution of 3-chloro-4-fluoroanisole (4.69 g, Lancaster) in chloroform (250 mL) was added silver trifluoroacetate (23.2 g, Aldrich) followed by iodine (15.8 g, Aldrich) in several portions. The reaction mixture was stirred for 2 hours and filtered through Celite. The filtrate was washed with water, brine, dried and concentrated. The crude product was purified by crystallization from ether/petroleum ether to give 5-chloro4-fluoro-2-iodoanisole (5.0 g). MS (M+H)+, 285.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[C:18]([C:23](O)=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[N:12]4[C:26](=[O:28])[NH:27][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1.[CH2:30]([NH2:32])[CH3:31].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[C:18]([C:23]([NH:32][CH2:30][CH3:31])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[N:12]4[C:26](=[O:28])[NH:27][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1cccnc1C(=O)O
Reactant: CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1ncccc1[C@H]1COc2c(-c3c(C)noc3C)ccc3[nH]c(=O)n1c23
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.8 %

Procedure:
A solution of 3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxylic acid (30.0 mg, 0.0764 mmol) (from step 2) in N,N-dimethylformamide (1.0 mL) was treated with ethylamine (10.8 μL, 0.191 mmol) followed by N,N-diisopropylethylamine (66.6 μL, 0.382 mmol) and stirred at room temperature for 5 min. The reaction mixture was subsequently treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate [Aldrich #: 226084](50.7 mg, 0.115 mmol) and stirred at room temperature for 1 h. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (23 mg, 71%) as a single enantiomer. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (t, J=5.9 Hz, 1H), 8.58 (dd, J=4.6, 1.4 Hz, 1H), 7.49 (dd, J=8.0, 4.6 Hz, 1H), 7.11 (dd, J=8.0, 1.2 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.54-6.41 (m, 1H), 4.64-4.45 (m, 2H), 3.43-3.24 (m, 2H), 2.24 (s, 3H), 2.07 (s, 3H), 1.15 (t, J=7.2 Hz, 3H); LCMS calculated for C22H22N5O4 (M+H)+: m/z=420.2. found: 420.2.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][CH2:43][CH:42]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][CH2:43][CH:42]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: CCOC(=O)C1CCCNC1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCCN(CCOc2cc3nccc(Oc4cc5ccccc5nc4C)c3cc2OC)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and ethyl piperidine-3-carboxylate (60 mg), and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (36 mg, yield 54%).
Reaction SMILES: Cl.[P:2]([OH:5])([OH:4])[OH:3].[C:6]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([OH:15])=[O:14])([OH:8])=[O:7].[CH2:16]=O>O>[C:6]([CH2:9][CH2:10][N:11]([CH2:16][P:2]([OH:5])([OH:4])=[O:3])[CH2:12][C:13]([OH:15])=[O:14])([OH:8])=[O:7]
Reactant: C=O
Reactant: OP(O)O
Reactant: O=C(O)CCNCC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)CCN(CC(=O)O)CP(=O)(O)O
Reaction time: 1 h
Yield: 52 %

Procedure:
In a three neck round bottom flask equipped with an addition funnel, a reflux condenser, and a stir bar was added 50 mL of water, 50 mL of concentrated hydrochloric acid, and 10.7 g (0.13 mol) of phosphorous acid. The solution was stirred and heated at reflux and then treated with 18.3 g (0.10 mol) of N-(2-carboxyethyl)glycine. Then 9.8 mL of a 40% (w/v) formaldehyde solution was added dropwise over 30 minutes. Heating was continued an additional 60 minutes. The solvent was then removed under reduced pressure until only a few mL remained. This was allowed to sit at 5° C. during which time a precipitate formed. This solid was filtered, washed with ethanol, and dried. The solvent was removed from the filtrate under reduced pressure. The residue was chromatographed on Dowex 50X8-400 ion exchange resin using water as the eluent. Combined with the initial precipitate, the ma3or fraction gave a total of 12.7 g (52%) of N-(2-carboxyethyl)-N-phosphonomethylglycine.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[N+:7]([C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][NH:16]2)=[CH:12][CH:11]=1)([O-])=O.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CC#N>[N:23]1([CH2:22][CH2:21][N:16]2[C:17]3[C:13](=[CH:12][CH:11]=[C:10]([NH2:7])[CH:18]=3)[CH:14]=[CH:15]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: ClCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc2ccn(CCN3CCOCC3)c2c1
Temperature: 25 °C

Procedure:
K2CO3 (5.08 g, 36.726 mmol) was added to a slurry of 6-nitroindole (1.985 g, 12.242 mmol), 4-(2-chloroethyl)morpholine hydrochloride (2.278 g, 12.242 mmol), and CH3CN (100 ml). The mix was heated at reflux for 18 h, then cooled to RT, filtered, and concentrated in vacuo. The crude was eluted through a silica gel column with a gradient of 3:97 to 5:95 and finally 8:92 MeOH:CH2Cl2, to yield upon drying 1-(2-morpholin-4-yl-ethyl)-6-nitro-1H-indole which was hydrogenated at regular condition described early to yield the title compound.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[C:10]([NH:11][C:12]2[C:13]3[CH2:28][O:27][CH2:26][C:14]=3[N:15]=[C:16]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[F:25])[N:17]=2)=[CH:9][CH:8]=[N:7][CH:6]=1)C.[OH-].[Na+]>CO>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]([F:25])=[C:18]([C:16]2[N:17]=[C:12]([NH:11][C:10]3[C:5]([C:4]([OH:29])=[O:3])=[CH:6][N:7]=[CH:8][CH:9]=3)[C:13]3[CH2:28][O:27][CH2:26][C:14]=3[N:15]=2)[CH:23]=1
Reactant: CCOC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1COC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1COC2
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluoro-phenyl)-5,7-dihydro-furo[3,4-d]pyrimidin-4-ylamino]-nicotinic acid ethyl ester (60 mg, 0.14 mmol, 1 eq) in MeOH (5 ml) was added a 1 N NaOH(aq) solution (300 μl, 0.30 mmol, 2 eq) and the reaction mixture was heated to reflux for 2 h. The solution was cooled to r.t. and concentrated in vacuo. Water (20 ml) was added to the crude material and the aqueous layer was acidified to pH 4. The solid was filtered, washed with water (2×5 ml) and dried overnight to afford 4-[2-(5-Chloro-2-fluoro-phenyl)-5,7-dihydro-furo[3,4-d]pyrimidin-4-ylamino]-nicotinic acid (50 mg, 90%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C@@H:11]1[C@H:17]2[C@H:18]3[C@H:27]([CH2:28][CH2:29][C@:14]2([CH2:15][CH3:16])[C:13](=[O:31])[CH2:12]1)[C@@H:26]1[C:21](=[CH:22][C:23](=[O:30])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3.O>N1C=CC=CC=1.C(Cl)Cl>[C:1]([O:10][C@@H:11]1[C@H:17]2[C@H:18]3[C@H:27]([CH2:28][CH2:29][C@:14]2([CH2:15][CH3:16])[C:13](=[O:31])[CH2:12]1)[C@@H:26]1[C:21](=[CH:22][C:23](=[O:30])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](O)CC2=O
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(=O)c1ccccc1)CC2=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
At 0° C., 5 ml of benzoyl chloride is added dropwise to 5 g of 15α-hydroxy-18-methyl-4-estrene-3,17-dione in 20 ml of pyridine. After 45 minutes, 2 ml of water is added, the mixture is stirred for another 30 minutes, and then the reaction mixture is poured into ice/water. The thus-precipitated product is suctioned off, dissolved in methylene chloride, washed with water, and dried over sodium sulfate. After chromatography of the crude product on silica gel with an acetone-hexane gradient, 5.6 g of 15α-benzoyloxy-18-methyl-4-estrene-3,17-dione is obtained as a foam.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][CH2:8][CH:7]2[CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19].C(N(CC)CC)C>CO.C1(C)C=CC=CC=1.[Pd]>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[C:7]2[CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19]
Reactant: CCC(=O)NCCC1CNCc2ccc(OC)cc21
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CO
Product: CCC(=O)NCCc1cncc2ccc(OC)cc12

Procedure:
The compound of Example 5 is dissolved in a minimum of methanol with the application of heat and then diluted with toluene. 1.5 equivalents of triethylamine are then added to the solution, and the reaction mixture is subsequently heated at reflux in the presence of palladium-on-carbon (10% by weight) for 3 hours. After removal of the catalyst by filtration, the solution is evaporated under reduced pressure. The oil obtained is purified by chromatography on silica gel (eluant dichlormethane/methanol 9/1). The purified oil is taken up in ether saturated with HCl(g) and stirred until a precipitate is obtained. The precipitate so formed is suction-filtered off and placed under vacuum in a dessicator. The title product is obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[H+].[B-](F)(F)(F)F.[CH3:17]COCC.[N+](=C[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N-].N#N>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[C:3]2[O:10][CH:17]=[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCOCC
Reactant: O=Cc1cccc(Br)c1O
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: F[B-](F)(F)F
Agent: N#N
Agent: [H+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1coc2c(Br)cccc12
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-2-hydroxybenzaldehyde (20 g, 0.1 mol) in 150 mL of CH2Cl2 was added HBF4.Et2O (1.5 mL, 0.01 mmol). A solution of ethyl diazoacetate (27.36 g, 0.24 mol) in CH2Cl2 (50 mL) was introduced into the reaction mixture, during about 3-6 min and the evolution of N2 gas observed, and the reaction was not allowed to go above 38° C. Once gas evolution ceased, the reaction mixture was concentrated by rotary evaporator and H2SO4 (20 mL) was added to the mixture while stirring. After 30 min, the mixture was diluted with CH2Cl2 (200 mL) and the H2SO4 was quenched with solid NaHCO3. The mixture was then filtered through silica gel (100 g), and concentrated by rotary evaporator to give an oil, then exacted with EtOAc (500 mL), and washed with brine (100 mL), dried over Na2SO4. The solvent was concentrated in vacuo. The residue was separated and purified with silica gel chromatography to give product ethyl 7-bromo-1-benzofuran-3-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH:29]=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[C:33]1=[O:47].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH2:29][N:44]3[CH2:45][CH2:46][CH:41]([N:34]4[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[N:32]([CH3:31])[C:33]4=[O:47])[CH2:42][CH2:43]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Reactant: Cn1c(=O)n(C2CCNCC2)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1c(=O)n(C2CCN(CCCn3nc(-c4ccc(C(F)(F)F)cc4)c4c3CCN(C(=O)OC(C)(C)C)C4)CC2)c2ccccc21
Reaction time: 0.33 h
Yield: 8.4 %

Procedure:
To a stirred solution of 1-(3-oxo-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.99 g, 23.6 mmol) in CH2Cl2 (20 mL) were added 1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.60 g, 25.9 mmol) and glacial AcOH (0.13 mL, 23.6 mmol) in that order and stirred for 20 min. NaBH(OAc)3 (0.65 g, 30.6 mmol) was added and stirred under nitrogen for 2 h. Saturated NaHCO3 (20 mL) was added and stirred for 30 min, and the layers were separated. The organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. MPLC of the crude afforded the desired compound as a white solid (1.27 g, 85%). TLC (silica, 7% MeOH/CH2Cl2): Rf=0.35. MS (electrospray): exact mass calculated for C34H41F3N6O3, 638.32. m/z found, 639.3 [M+H]+, 661.2 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.81 (br d, J=8.0 Hz, 2H), 7.68 (br s, 2H), 7.25 (dd, J=1.6, 7.5 Hz, 1H), 7.15-7.07 (m, 2H), 7.02(dd, J=1.6, 7.9 Hz, 1H), 4.70 (br s, 2H), 4.38 (tt, J=4.2, 12.4 Hz, 1H), 4.18 (t, J=6.8 Hz, 2H), 3.82 (s, 2H), 3.45 (s, 3H), 3.07 (d, J=11.6 Hz, 2H), 2.84 (t, J=5.5 Hz, 2H), 2.53-2.42 (m, 2H), 2.44 (t, J=6.7 Hz, 2H), 2.21-2.03 (m, 4H), 1.84 (d, J=12.0 Hz, 2H), 1.52 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([CH2:11][NH2:12])[O:7][C:6]=2[C:13]=1[CH3:14].[N+:15]([C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[O:21][CH2:22][CH2:23][CH2:24]Br)([O-])=O.C(N(C(C)C)CC)(C)C.Cl>CN(C=O)C.CO.[Pd]>[NH2:15][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[O:21][CH2:22][CH2:23][CH2:24][NH:12][CH2:11][CH:8]1[O:7][C:6]2[C:13]([CH3:14])=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9]1
Reactant: Cc1c(O)ccc2c1OC(CN)CO2
Reactant: O=[N+]([O-])c1cccc(OCCCBr)c1
Agent: [Pd]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1c(O)ccc2c1OC(CNCCCOc1cccc(N)c1)CO2
Temperature: 80 °C
Yield: 25.8 %

Procedure:
2,3-Dihydro-7-hydroxy-8-methyl-1,4-benzodioxin-2-methanamine (0.70 g, 3.6 mmole), 3-(3-nitrophenoxy)propyl bromide (0.94 g, 3.6 mmole) and diisopropylethylamine (0.47 g, 3.6 mmole) were combined in 50 ml of DMF and heated at 80° C. for 24 hrs. under a nitrogen atmosphere. The solvent was then removed in vacuum and the residue dissolved in chloroform and washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel using first chloroform and then 2% methanol/chloroform as eluant. The product-containing fractions were combined and concentrated in vacuum to give a dark yellow oil. This was dissolved in methanol (100 ml) and 0.5 g of 10% palladium on carbon added, along with 5 ml of 4N isopropanolic HCl. The mixture was hydrogenated at 50 psi on a Parr apparatus overnight, filtered through celite, concentrated in vacuum. to an off-white solid and column chromatographed on silica gel with 5% methanol/chloroform (with 1 ml/liter aqueous ammonia added). The product-containing fractions were combined and evaporated in vacuum and recrystallized from isopropanol with addition of 4N HCl/IPA to give 0.32 g of title compound as a yellow solid, dihydrochloride, hydrate, isopropanol solvate, m.p. 156° C. (d).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]Cl)[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(Cl)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Cl)nc1CN1CCOCC1

Procedure:
Methyl 6-chloro-2-(chloromethyl)pyridine-3-carboxylate (1.5 g, 6.82 mmol) and potassium carbonate (1.13 g, 8.18 mmol) were taken up in DMF (13 mL) and morpholine (0.59 mL, 6.82 mmol) was added. The mixture was allowed to react at room temperature overnight, at which time water was added and the products extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as an orange oil.
Reaction SMILES: Cl.[CH2:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21][O:22][C:23](=[O:27])[CH2:24][CH2:25]Br.[OH-].[Na+:29]>>[CH3:21][O:22][C:23](=[O:27])[CH2:24][CH2:25][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1.[Na+:29].[CH2:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:25][CH2:24][C:23]([O-:27])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)CCBr
Reactant: c1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)CCN1CCN(c2ccc(Cc3ccccc3)cc2)CC1
Product: O=C([O-])CCN1CCN(c2ccc(Cc3ccccc3)cc2)CC1
Yield: 42.6 %
Yield: 89.5 %

Procedure:
3-[4-(4-Benzyl-phenyl)-piperazin-1-yl]-propionic acid methyl ester (120 mg, 42.6%) was prepared from 1-(4-Benzyl-phenyl)-piperazine hydrochloride (250 mg, 0.77 mmol) and 3-bromo-propionic acid methyl ester (128 mg, 0.77 mmol) using the method described in Example 5. Following the procedure described in Example 2, the ester (120 mg, 0.35 mmol) was treated with 1N NaOH (0.43 mL, 0.43 mmol) to yield the title compound (110 mg, 89.5%): MS (ESI) m/z 325 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 2.02 (t, J=7.6 Hz, 2H), 2.43-2.51 (m, 6H), 3.03 (t, J=4.8 Hz, 4H), 3.81 (s, 2H), 6.83 (d, J=8.8 Hz, 2H), 7.04 (d, J=8.8 Hz, 2H), 7.14-7.19 (m, 3H), 7.26 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][O:7][C:8]2[C:9]([O:35][CH3:36])=[CH:10][C:11]([CH:14]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[N:18]([Si](C(C)C)(C(C)C)C(C)C)[CH:17]=3)[OH:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][O:7][C:8]2[C:9]([O:35][CH3:36])=[CH:10][C:11]([C:14]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)=[O:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)ncc1OCc1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c[nH]c3ncccc23)ncc1OCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
[5-(4-Chloro-benzyloxy)-4-methoxy-pyridin-2-yl]-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (642, 60.0 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2.00 mL). Dess-Martin periodinane (55.3 mg, 0.13 mmol) was added to the reaction and it was stirred at room temperature overnight. The mixture was extracted with ethyl acetate and saturated sodium bicarbonate. The organic portions were dried with anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto silica and purified by silica gel chromatography, methanol:dichloromethane, to provide the desired compound (P-2024, 10.7 mg, 25%). 1H-NMR was consistent with the desired compound. MS (ESI) [M+H+]+=394.1, 396.1.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:14][CH3:15])[CH:5]=1)(=[O:3])[NH2:2].C(Cl)(=O)[C:17](Cl)=[O:18]>C(Cl)CCl>[N:2]([C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3])=[C:17]=[O:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(C(N)=O)cc1OC
Solvent: ClCCCl
Product: COC(=O)c1ccc(C(=O)N=C=O)cc1OC
Yield: 63.6 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using methyl 4-carbamoyl-2-methoxybenzoate (1.4 g, 6.69 mmol), oxalyl chloride (0.72 mL, 8.03 mmol) and EDC (10 mL) to afford 1.00 g of the desired product.
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.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH3:40])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:17]([NH:16][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)[CH2:18][NH:19][CH3:32])=[CH:34][C:35]=1[CH3:40]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: Cc1cc([C@H](N)CN(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)ccc1Cl
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(Cl)c(C)c1

Procedure:
Compound 44 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-chloro-3-methyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [371 (M+H)]; 1H NMR (500 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.08 (s, 1H), 8.99 (d, J=4.3 Hz, 1H), 8.53 (s, 1H), 8.37 (d, J=4.3 Hz, 1H), 8.17 (s, 1H), 7.43 (s, 1H), 7.34 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 5.54-5.26 (m, 1H), 3.21-3.03 (m, 1H), 3.00-2.77 (m, 1H), 2.30 (s, 6H), 1.78 (s, 1H).