Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14][CH3:15])[C:3]=1[CH2:16][C:17]([C:38]([O:40][CH2:41][CH3:42])=[O:39])([CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][CH:28]=1)[C:18]([O:20]CC)=O.C([Li])CCC.C(O)(=O)C>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH2:36]([O:35][C:33]([C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][CH2:23][C:17]2([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:16][C:3]3[C:2](=[C:7]([O:8][CH3:9])[C:6]([O:10][CH3:11])=[C:5]([O:12][CH3:13])[C:4]=3[O:14][CH3:15])[C:18]2=[O:20])=[CH:28][CH:29]=1)=[O:34])[CH3:37]
Reactant: CCOC(=O)c1ccc(OCCCC(Cc2c(Br)c(OC)c(OC)c(OC)c2OC)(C(=O)OCC)C(=O)OCC)cc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(OCCCC2(C(=O)OCC)Cc3c(OC)c(OC)c(OC)c(OC)c3C2=O)cc1
Temperature: -78 °C
Yield: 91.7 %

Procedure:
To a solution of ethyl 3-(2-bromo-3,4,5,6-tetramethoxyphenyl)-2-ethoxycarbonyl-2-[3-(4-ethoxycarbonylphenoxy)propyl]propionate (40.0 g) in THF (400 ml) was dropwise added n-butyl lithium in hexane (1.68M; 41.8 ml) under nitrogen atmosphere at −100° C. or under and the solution was allowed to warm to −78° C. in 30 min. The reaction mixture was cooled to −100° C. again and a solution of acetic acid (7.33 g) in THF (20 ml) was dropwise added, which was then allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=7:1) to yield the entitled compound (29.7 g) as an oil.
Reaction SMILES: C[O-].[Na+].C([O:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([S:24]([NH2:27])(=[O:26])=[O:25])[C:13]2[C:18]([C:19]=1[Br:20])=[CH:17][CH:16]=[CH:15][C:14]=2[N+:21]([O-:23])=[O:22])(=O)C>CO>[Br:20][C:19]1[C:18]2[C:13](=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=[CH:16][CH:17]=2)[C:12]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:11][C:10]=1[CH2:9][CH2:8][OH:7]
Reactant: CC(=O)OCCc1cc(S(N)(=O)=O)c2c([N+](=O)[O-])cccc2c1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NS(=O)(=O)c1cc(CCO)c(Br)c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium methoxide in methanol (23.7 mL of a 0.5M solution, 11.8 mmol) was added to a suspension of 3-(2-acetoxy-ethyl)-4-bromo-8-nitro-naphthalene-1-sulfonamide (4.70 g, 11.3 mmol) in methanol (33 mL). The mixture was stirred under a nitrogen atmosphere at room temperature for 90 minutes, then concentrated under vacuum to approximately half volume, diluted with ethyl acetate (200 mL), and washed with 2N hydrochloric acid. The oganic solution was washed with water (100 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and left to stand at room temperature. The organic solution deposited a solid which was collected by filtration, washed with ethyl acetate (2×15 mL), and vacuum dried to give the title comound (1.78 g). Additional poduct (1.88 g) was obtained from the mother liquors after concentration under vacuum and crystallization from diethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9]CC)=O.[CH3:12][C:13]([CH3:15])=[O:14].CC(C)([O-])C.[K+].C(O)(=O)C>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7](=[O:9])[CH2:12][C:13](=[O:14])[CH3:15]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1occc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)CC(=O)c1occc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-bromofuran-2-carboxylate (16.2 g) and acetone (5.14 mL) in toluene (250 mL) was added potassium tert-butoxide (15.7 g) at 0° C. portionwise. The reaction mixture was stirred at room temperature for 2 hr, and acetic acid (8.01 mL) and water (250 mL) were added. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from hexane/ethyl acetate to give the title compound (10.9 g, enol/diketone=88/12).
Reaction SMILES: [CH3:1][N:2]([C:26]([C:28]1[N:29](CC2C=CC=CC=2)[CH:30]=[C:31]([O:35]CC2C=CC=CC=2)[C:32](=[O:34])[CH:33]=1)=[O:27])[NH:3][S:4]([NH:7][C:8]([N:10]1[CH2:13][C@H:12]([NH:14]C(OCC2C=CC=CC=2)=O)[C:11]1=[O:25])=[O:9])(=[O:6])=[O:5].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53]>CN(C)C=O.[Pd]>[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[NH2:14][CH:12]1[CH2:13][N:10]([C:8]([NH:7][S:4]([NH:3][N:2]([CH3:1])[C:26]([C:28]2[NH:29][CH:30]=[C:31]([OH:35])[C:32](=[O:34])[CH:33]=2)=[O:27])(=[O:5])=[O:6])=[O:9])[C:11]1=[O:25]
Reactant: CN(NS(=O)(=O)NC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O)C(=O)c1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CN(NS(=O)(=O)NC(=O)N1CC(N)C1=O)C(=O)c1cc(=O)c(O)c[nH]1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 2 g of (S)-1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinecarboxylic acid, 1-methyl-2-[[[[2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinyl]carbonyl]amino]sulfonyl]hydrazide in 60 ml of dimethylformamide, 1.1 ml of trifluoroacetic acid was added, followed by one gram of palladium on charcoal (10%). After flushing with nitrogen, hydrogen was passed through the solution for 60 minutes with stirring, the catalyst was removed by filtration, the filtrate evaporated in vacuo and the residue triturated with ether to yield 1.1 g of crude title compound. Yield: 86.6%.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH:24]([CH3:26])[CH3:25])[O:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[CH2:32][CH2:31]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH:24]([CH3:26])[CH3:25])[O:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:41]([C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)=[CH:44][CH:43]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)c1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)co1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)c1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCOCC6)cc5)nc34)CC2)co1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-((2-isopropyloxazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.065 g, 0.15 mmol), EtOH (0.85 mL), and DMF (0.15 mL), was added 4-(morpholinomethyl)benzaldehyde (0.040 g, 0.19 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.49 mL, 0.49 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was purified by column chromatography on a Biotage SP1 system eluting with methanol (10-30%) in ethyl acetate. The title compound was isolated as a pale yellow solid (0.002 g, 2.4%) after trituration with ether; 1H-NMR (500 Mz, DMSO-d6): δ 1.27 (d, J=7 Hz, 6H, iPr—CH3), 2.38 (m, 4H), 2.65 (m, 4H), 3.05 (m, 1H, iPr—CH), 3.44 (s, 2H, NCH2), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.66 (m, 4H), 7.47 (d, J=7.5 Hz, 2H, ArH), 7.87 (s, 1H, oxazole 5-H), 8.14 (d, J=8.0 Hz, 2H, ArH), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.49 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.43 min—580/582 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 580.2036, calculated for C28H35BrN7O2 (M+H)+: 580.2035.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:20](O)[CH2:21][CH2:22][OH:23]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)=[C:9]([CH:10]2[O:23][CH2:22][CH2:21][CH2:20][O:11]2)[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCCO
Reactant: CC1(C)COC(c2ccc(C(C)(C)C)cc2C=O)=N1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: CC1(C)COC(c2ccc(C(C)(C)C)cc2C2OCCCO2)=N1
Temperature: 25 °C
Yield: 49.8 %

Procedure:
8.10 g (31.2 mmol) of 5-tert-butyl-2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-benzaldehyde was weighed into a 500 mL round bottom flask fitted with a stir bar and Dean-Stark trap. Added 300 mL of benzene and stirred to obtain a clear yellow solution. Added 383 mg (1.52 mmol) of pyridinium p-toluenesulfonate. Added 11.3 mL (156 mmol) of 1,3-propanediol. Heated the solution to reflux for 17 h. Cooled to room temperature Washed the reaction mixture with 200 mL of 50% saturated aqueous NaHCO3, 200 mL of water, and 200 mL brine. Dried over MgSO4 and removed the solvent on rotavap. Purified by silica gel flash chromatography using isocratic elution with 10% EtOAc/CH2Cl2 to obtain 4.93 g of the title compound as a clear yellow resin. MS (ESI) 318 (M+H)+.
Reaction SMILES: [Cl-].[OH:2][C@H:3]([C:15]1[CH:24]=[CH:23][C:18]2[C:19](=[O:22])[O:20][CH2:21][C:17]=2[C:16]=1[CH3:25])[CH2:4]N1CC2(CCCC2)[NH2+]CC1>C(O)C>[CH3:25][C:16]1[C:17]2[CH2:21][O:20][C:19](=[O:22])[C:18]=2[CH:23]=[CH:24][C:15]=1[C@@H:3]1[CH2:4][O:2]1
Reactant: Cc1c([C@@H](O)CN2CC[NH2+]C3(CCCC3)C2)ccc2c1COC2=O
Agent: [Cl-]
Solvent: CCO
Product: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Yield: 100 %

Procedure:
A solution of 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1 (3H)-one (INTERMEDIATE 2) (38 mg, 0.20 mmol) in 0.50 mL of ethanol was prepared. Separately, 9-[(2R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-9-aza-6-azoniaspiro[4.5]decane Chloride (INTERMEDIATE 3)(60. mg, 0.20 mmol) was dissolved in 1 mL of ethanol by addition of 200 mg of MP-CO3 resin and heating. The two solutions, along with the resin, were combined and microwaved at 140° C. for fifty-five minutes. The solvent was removed in vacuo and the remaining solids were dissolved in 1 mL DMSO.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1>Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CNc1ccc(Cl)cc1
Agent: Cl
Product: CN(c1ccc(Cl)cc1)c1ncccc1[N+](=O)[O-]

Procedure:
To 90 g (0.63 mole) of 4-chloro-N-methylaniline heated to 115°-120° C. under nitrogen atmosphere with stirring was added 66.3 g (0.42 mole) of 2-chloro-3-nitropyridine in four portions over a period of 80 minutes. After stirring the reaction mixture for an additional 20 minutes at 115°-120° C., the temperature was increased to 135°-140° C. for an additional 20 minute period. The hot melt was poured into 700 ml of 2N hydrochloric acid solution. Red precipitate weighing 96 g was collected and dissolved in hot acetic acid and converted to the hydrochloride salt by adding etheral hydrogen chloride. The yield of the yellow solid was 90 g (72%). A portion of the salt was recrystallized from ethyl acetate-ethyl alcohol. On drying at 80° C. in vacuo, the hydrochloride salt dissociated to the free base, the title compound, m.p. 107°-110° C.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([NH:25][CH2:26][C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)[N:10]4[N:9]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: NCc1cccnc1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CN1CCN(c2ccc(Nc3ncc4ccc(NCc5cccnc5)n4n3)cc2)CC1
Temperature: 120 °C

Procedure:
Into a 8-dram vial, (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (66.6 mg, 0.000172 mol), [3-(Aminomethyl)-pyridine (22.33 mg, 0.2065 mmol) Palladium Acetate (4.00 mg, 0.0178 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (30.0 mg, 0.0518 mmol), and Cesium Carbonate (240.0 mg, 0.7366 mmol) were added. The mixture was purged with nitrogen for 15 minutes. 1,4-Dioxane (2.00 mL) was added. The reaction vessel was sealed and heated at 120° C. for 2 hours. The reaction mixture was partitioned with DCM. The solid was filtered through celite and washed with DCM. The filtrate was evaporated to give a semi-solid. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN (0 to 20% ACN). The collected fractions were lyophilized to give N(2)-[4-(4-Methyl-piperazin-1-yl)-phenyl]-N(7)-pyridin-3-ylmethyl-pyrrolo[2,1-f][1,2,4]triazine-2,7-diamine a solid. The solid was triturated with Et2O to give a yellow solid 78 mg, 85%). LCMS (E/I+) 415.17 (M+H). NMR 1H (DMSO-d6)-9.80 (bs, 1H), 9.34 (s, 1H), 8.70 (s, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 7.89 (d, 1H, J=7.04 Hz), 7.65 (d, 2H, J=8.04 Hz), 7.54 (t, 1H, J=5.53 Hz), 7.49 (bs, 1H), 7.13 (s, 1H), 6.99 (d, 2H, J=8.04 Hz), 6.33 (s, 1H), 4.72 (s, 2H), 3.75 (d, 2H, J=12.56 Hz), 3.54 (d, 2H, J=11.06 Hz), 3.18 (bs, 2H), 2.6-3.00 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH2:33][CH2:32]1)=[O:19])=[N:5]2
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Product: COc1ccccc1N1CCN(C(=O)Nc2nc3cc(Cl)ccc3nc2OC)CC1
Yield: 77 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 77%). 1H NMR (300 MHz, CDCl3): δ 3.10-3.17 (m, 4H), 3.80-3.89 (m, 6H), 4.08-4.15 (m, 4H), 6.88-7.07 (m, 4H), 7.20-7.32 (m, 1H), 7.41-7.44 (m, 1H), 7.50-7.68 (m, 1H), 7.82 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=2[Cl:19])[C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:38][CH2:37][CH2:36][S:35]3(=[O:40])=[O:39])=[CH:30][CH:29]=2)O1>>[Cl:19][C:12]1[C:13]([F:18])=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH2:10][O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH2:38][CH2:37][CH2:36][S:35]3(=[O:40])=[O:39])=[CH:32][CH:33]=2)[CH:3]=1
Reactant: Nc1ncc(Br)cc1OCc1c(F)ccc(F)c1Cl
Reactant: CC1(C)OB(c2ccc(N3CCCS3(=O)=O)cc2)OC1(C)C
Product: Nc1ncc(-c2ccc(N3CCCS3(=O)=O)cc2)cc1OCc1c(F)ccc(F)c1Cl

Procedure:
3-(2-Chloro-3,6-difluoro-benzyloxy)-5-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-phenyl]-pyridin-2-ylamine was prepared following procedure 3 from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]isothiazolidine 1,1-dioxide.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=[O:20])[C:3]=1[CH3:21].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:33]([NH2:34])=[CH:32][C:31]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:30][N:29]=2)[CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[N:25]1([C:28]2[C:33]([NH:34][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([N:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]4=[O:20])[C:3]=3[CH3:21])=[CH:32][C:31]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[CH:30][N:29]=2)[CH2:24][CH2:23][O:22][CH2:27][CH2:26]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-n2ccccc2=O)nc2cc(F)cc(F)c2c1Br
Solvent: Cc1ccccc1
Product: Cc1c(-n2ccccc2=O)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Essentially prepared according to Procedure H using 1-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)pyridin-2(1H)-one (50.0 mg, 0.140 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give 1-(4-((2,5-di-4-morpholinyl-3-pyridinyl)amino)-5,7-difluoro-3-methyl-2-quinolinyl)-2(1H)-pyridinone. 1H NMR (CDCl3) δ ppm 8.29 (1H, dd, J=4.8, 1.1 Hz), 7.80-7.88 (1H, m), 7.72 (1H, d, J=10.2 Hz), 7.62 (1H, d, J=2.5 Hz), 7.27-7.33 (1H, m), 7.14-7.23 (2H, m), 6.91 (1H, ddd, J=13.3, 8.9, 2.4), 6.35 (1H, d, J=2.2 Hz), 3.92 (4H, br. s.), 3.76-3.83 (4H, m), 3.12-3.46 (4H, m), 2.98-3.07 (4H, m), 2.15 (3H, s). Mass Spectrum (ESI) m/e=535.2 (M+1).
Reaction SMILES: O1C2C=CC=CC=2OB1.[CH2:10]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:28]([Br:29])=[C:27]([CH3:30])[N:26]=[C:25]([CH3:31])[C:24]=2[C:32](=[O:39])[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[CH2:10]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:28]([Br:29])=[C:27]([CH3:30])[N:26]=[C:25]([CH3:31])[C:24]=2[C@H:32]([OH:39])[C:33]([O:35][CH:36]([CH3:37])[CH3:38])=[O:34])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(Cc3ccccc3)CC2)c1Br
Agent: B1Oc2ccccc2O1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Product: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CCC(Cc3ccccc3)CC2)c1Br
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
The 1.3 mL of benzo[d][1,3,2]dioxaborole (709 mg, 5.91 mmol) was added to a nitrogen purged solution of isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-oxoacetate (1.4 g, 2.96 mmol) and 1.2 mL of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (328 mg, 1.18 mmol) in toluene (30 mL) at −60° C. and allowed to warm to −15° C. before being placed in the freezer overnight. The reaction was quenched with 1M Na2CO3, diluted with EtOAc, and stirred for 30 min. The organic layer was washed with sat'd Na2CO3 solution, brine and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (0-50% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate as a mixture of diastereomers 1.4 g (100%). 1H NMR (500 MHz, DMSO-d6) δ 7.30-7.27 (m, 2H), 7.19-7.18 (m, 3H), 5.95/5.93 (s, 1H), 4.97-4.93 (m, 1H), 3.53 (t, J=11.4 Hz, 1H), 3.40-3.38 (m, 1H), 3.31 (t, J=11.7 Hz, 1H), 3.25 (br. s, 1H), 2.87 (d, J=10.3 Hz, 1H), 2.77 (d, J=10.6 Hz, 1H), 2.55/2.54 (s, 3H), 2.38 (s, 3H), 1.60-1.52 (m, 3H), 1.38-1.63 (m, 2H), 1.14 (d, J=5.9 Hz, 3H), 1.05 (d, J=5.9 Hz, 3H). UPLC (M+H)=477.1.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([S:15]([NH:18][C@H:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.COC(=O)[C@@H](C(C)C)N>O1CCOCC1.C(Cl)Cl>[N:12]1([S:15]([NH:18][C@H:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]1
Reactant: COC(=O)[C@@H](C)NS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: COC(=O)[C@H](N)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](C)NS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
Hydrogen chloride gas was bubbled through a solution of methyl 2-(R)-[(4-tert-butoxycarbonylpiperazine-1-sulfonyl)amino]propionate (3.6 g, 10.7 mmol) [prepared by proceeding as described in Example 2, but substituting 4-(5-chloropyridin-2-yloxy)piperidine and D-valine methyl ester with 1-tert-butoxycarbonyl-1,4-piperazine and D-alamine methyl ester, respectively] in 10% dioxane/methylene chloride (100 ml) for 10 min. The reaction was stirred at RT for 4 h and concentrated in vacuo to give methyl 2-(R)-[(piperazine-1-sulfonyl) amino]propionate (91%) as a white solid that was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[C:13]([CH2:14][OH:15])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:16].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>CC(C)=O>[CH3:22][O:21][C:19](=[O:20])[CH2:18][O:16][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][OH:15])[C:8]=1[Cl:7]
Reactant: OCc1cccc(O)c1Cl
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)COc1cccc(CO)c1Cl
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
Cesium carbonate (3.42 g, 10.5 mmol) was added to a solution of 2-chloro-3-hydroxymethylphenol (1.59 g, 10 mmol) in acetone at room temperature, and the reaction mixture allowed to stir for 30 minutes. Methyl bromoacetate (1.68 g, 11 mmol) was then added. The mixture was stirred overnight, filtered, and the filtrate was concentrated in vacuo. Purification of the residue by silica gel flash chromatography, eluting with dichloromethane/methanol, gave (2-chloro-3-hydroxymethylphenoxy)acetic acid methyl ester as a white crystalline solid (1.94 g, 84.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10]([N:17]=[CH:18][N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.NC1[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:25]([O:38][CH3:39])[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([C:21]4[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])=[C:25]([O:38][CH3:39])[CH:24]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(N)ccc1OCC(=O)OC(C)(C)C
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(=O)OC(C)(C)C
Yield: 34 %

Procedure:
Condensation of methyl 5-(4-chlorophenyl)-3-((dimethylamino)methylene-amino)-thiophene-2-carboxylate (740 mg) and tert-butyl 2-(4-amino-2-methoxy-phenoxy)acetate Part C (581 mg) as described in Example 1 yielded the title compound 388 mg (34%). 1H NMR (CDCl3) δ 1.50 (s, 9H), 3.92 (s, 3H), 4.65 (s, 2H), 6.91 (br s, 2H), 6.99 (br s, 1H), 7.44 (d, J=8.24 Hz, 2H), 7.53 (s, 1H), 7.65 (d, J=8.25 Hz, 2H), 8.14 (s, 1H); 13C NMR (CDCl3) δ 28.04, 56.21, 66.57, 82.58, 111.28, 113.76, 118.98, 120.86, 123.21, 127.65, 129.45, 130.85, 131.52, 135.68, 148.12, 150.00, 151.66, 156.73, 157.36, 167.51; HPLC (Method #1): 3.89 min retention time; MS (ES): m/z 499 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([CH:10]=[CH2:11])([CH:8]=[CH2:9])[CH:6]=[CH2:7].[C:12]([O-:15])(=[O:14])[CH3:13].[Na+]>CN(C)C=O>[C:12]([O:15][CH2:2][CH2:3][CH2:4][Si:5]([CH:10]=[CH2:11])([CH:8]=[CH2:9])[CH:6]=[CH2:7])(=[O:14])[CH3:13]
Reactant: C=C[Si](C=C)(C=C)CCCCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C[Si](C=C)(C=C)CCCOC(C)=O
Temperature: 120 °C
Yield: 76 %

Procedure:
As shown in Reaction Scheme 24, 3-chloropropyltrivinylsilane (1.0 g, 5.35 mmol) and sodium acetate (0.87 g, 10.7 mmol) were dissolved in 17 mL of dimethylformamide (DMF), and the reaction mixture was heated at 120° C. for 12 hours. After the reaction, the organic layer was separated after addition of distilled water and ether. The organic layer was dried over MgSO4, concentrated by evaporation of solvent, and the resulting residue was purified by column chromatography (n-Hex: EA=10:1, Rf=0.4) to give 855 mg (76% yield) of pure 3-acetoxypropyltrivinylsilane.