Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[N:30]1([CH:36]2[CH2:41][CH2:40][N:39]([C:42]3[CH:43]=[C:44]([NH2:48])[CH:45]=[CH:46][CH:47]=3)[CH2:38][CH2:37]2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>COCCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:48][C:44]3[CH:45]=[CH:46][CH:47]=[C:42]([N:39]4[CH2:40][CH2:41][CH:36]([N:30]5[CH2:31][CH2:32][O:33][CH2:34][CH2:35]5)[CH2:37][CH2:38]4)[CH:43]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: Nc1cccc(N2CCC(N3CCOCC3)CC2)c1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(N4CCC(N5CCOCC5)CC4)c3)nn12
Yield: 13.7 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (85.0 mg, 0.000296 mol), N,N-Diisopropylethylamine (0.0773 mL, 0.000444 mol) and 3-(4-Morpholin-4-yl-piperidin-1-yl)-phenylamine (155 mg, 0.000592 mol) were dissolved in 2-Methoxyethanol (2.08 mL) and The reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to provide 19.65 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-amine as a lyophilized powder. (M+H)=485.25. 1H NMR (400 MHz, DMSO, d6) δ 9.22 (s, 1H), 8.95 (s, 1H), 7.71 (m, 1H), 7.50 (t, 1H, J=6.88 Hz), 7.32 (m, 1H), 7.21 (m, 1H), 7.09 (m, 3H), 6.90 (q, 2H, J=5.65 Hz), 6.53 (m, 1H), 4.02 (m, 2H), 3.76 (s, 3H), 3.68 (t, 2H, J=12.16 Hz), 3.56 (m, 2H), 3.48 (m, 2H), 3.21 (m, 1H), 3.10 (m, 2H), 2.53 (m, 2H), 2.04 (m, 2H), 1.60 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)N.[BrH:14].N([O-])=O.[Na+]>O>[Br:14][C:4]1[CH:6]=[C:7]([F:9])[CH:8]=[C:2]([F:1])[C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: Br
Reactant: Nc1cc(F)cc(F)c1C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1cc(F)c(C(F)(F)F)c(Br)c1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
A suspension of 3,5-difluoro-2-(trifluoromethyl)aniline (24, 1.0 g, 5.07 mmol) in a 48% aqueous HBr (8 mL) and H2O (8 mL) was stirred at −5° C. for 5 min. To the suspension, NaNO2 (350 mg, 5.07 mmol) was added in a 10 mL aqueous solution dropwise maintaining −5° C. The resulting mixture was stirred at −5° C. for 1 h then CuBr (1.09 g, 7.63 mmol) was added portion-wise and the resulting suspension was allowed to slowly warm to ambient temperature. After 4 hours, the resulting solution was extracted with hexanes (3×75 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (40 g Redisep column, pure hexanes) to afford 1-bromo-3,5-difluoro-2-(trifluoromethyl)benzene (25) as a light yellow liquid (1.01 g, 68%). 1H NMR (300 MHz, CDCl3) δ 7.34-7.28 (m, 1H), 6.99-6.85 (m, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]([OH:25])([CH3:24])[CH3:23])[N:19]=[C:18]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[Br:36]N1C(=O)CCC1=O>CC#N.CCOC(C)=O>[Br:36][C:21]1[N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=3)=[CH:12][CH:13]=2)[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])=[N:19][C:20]=1[C:22]([OH:25])([CH3:24])[CH3:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2C(F)(F)F)n1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(O)c1nc(-c2ccccc2C(F)(F)F)n(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c1Br
Reaction time: 2 h
Yield: 86291.9 %

Procedure:
To a solution of 2-[1-(3′-methanesulfonyl-biphenyl-4-yl)-2-(2-trifluoromethyl-phenyl)-1H-imidazol-4-yl]-propan-2-ol (100 mg, 0.20 mmol) in MeCN (2 mL, anhyd) was added N-bromosuccinimide (45 mg, 0.25 mmol). After 2 h, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, water (3×10 mL) and brine, then dried (Na2SO4) and concentrated. The residue was purified by chromatography (silica), eluting with EtOAc/hexanes (65:40 to 95:5) to yield the title compound (100 g, 86%) as a white solid. 1H-NMR (CD2Cl2): δ 8.10 (1H, m), 7.92 (1H, m), 7.86 (1H, m), 7.60-7.74 (4H, m), 7.47 (2H, m), 7.25-7.31 (3H, m), 3.56 (1H, s), 3.06 (3H, s), 1.66 (6H, s); MS (ES): 579, 581 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7](=[O:12])(OC)[O:8][CH3:9].[NH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20].O>O1CCCC1>[CH3:20][C:19]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH:13][C:7](=[O:12])[O:8][CH3:9]
Reactant: Cc1ccncc1N
Reactant: COC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Nc1cnccc1C
Temperature: 17.5 °C
Yield: 88.2 %

Procedure:
Potassium tert-butoxide (10.3 g, 92.5 mmol) in tetrahydrofuran (25 mL) was stirred at 23 to 27° C. for 30 minutes, and dimethyl carbonate (4.67 mL, 55.5 mmol) was added while the temperature was kept at 35° C. or below. To the reaction mixture, 3-amino-4-methylpyridine (5.00 g, 46.2 mmol) in tetrahydrofuran (40 mL) stirred at 32 to 38° C. for 90 minutes was added dropwise at 20 to 35° C. over 2 hours with stirring. The resulting reaction mixture was cooled to 15 to 20° C., stirred with water (25 mL) at 25° C. or below for 1 hour and extracted with tetrahydrofuran. The organic layer was azeotropically distilled with toluene under reduced pressure to a volume of about 50 mL and stirred at 23 to 27° C. for one day. The precipitated solid was collected by filtration, washed with toluene and dried under reduced pressure to give the title compound as a brown solid (6.77 g, yield 88%).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]([CH2:22][CH:23]([C:28]([O:30]C)=[O:29])[C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CO.O1CCCC1>[CH3:27][O:26][C:24]([CH:23]([CH2:22][C:21]1[CH:32]=[CH:33][C:18]([O:17][CH2:16][CH2:15][O:14][C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:34])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[CH:19][CH:20]=1)[C:28]([OH:30])=[O:29])=[O:25]
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of dimethyl 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]benzylmalonate (0.50 g, 1.07 mmol) in a mixture of methanol (4.3 ml) and tetrahydrofuran (2.1 ml) at 0° C. is added a 2 mol/L aqueous solution of sodium hydroxide (0.59 ml, 1.18 mmol). The mixture is stirred for 2 hours at room temperature, and then the solvent was removed under a vacuum. The residue is dissolved in saturated aqueous sodium bicarbonate (10 ml) and washed with ethyl acetate (10 ml). The aqueous solution is acidified to pH 2–3 with dilute hydrochloric acid and extracted with ethyl acetate (3×15 ml). The combined extracts are washed with water (20 ml) and brine (20 ml), dried over sodium sulfate, and concentrated. The residue is crystallized from ethyl acetate to give the title compound (0.45 g, 93%). HRMS calcd for C27H34O6: 454.5634. Found: 454.5636. MA calcd for C27H34O6: C, 71.34%; H, 7.54%. Found: C, 71.42%; H, 7.52%.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][CH:27]([CH3:32])[CH2:28][C:29](O)=[O:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[CH2:28][CH:27]([CH3:32])[CH3:26])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: CC(C)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, light yellow solid (9.1 mg, 31.4%), MS (ISP) m/z=415.5[(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.07 mmol) and 3-methylbutanoic acid
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9](OCC)OCC)=[CH:4][C:3]=1[F:17].C(=O)(O)O.[NH2:22][NH:23][C:24]([NH2:26])=[NH:25].[OH-].[K+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:22]=[N:23][C:24]([NH2:26])=[N:25][CH:9]=2)=[CH:4][C:3]=1[F:17]
Reactant: N=C(N)NN
Reactant: CCOC(OCC)C(=O)c1ccc(Br)c(F)c1
Agent: O=C(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Temperature: 110 °C

Procedure:
A mixture of 1-(4-bromo-3-fluorophenyl)-2,2-diethoxyethanone (Step 4, 15.2 g, 50 mmol), aminoguanidine bicarbonate (10.2 g, 75 mmol) and potassium hydroxide (6.6 g, 100 mmol) in ethanol (200 mL) and water (4 mL) was refluxed overnight. The solvent was evaporated under reduced pressure and the residue was washed with acetonitrile and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), washed with water, brine, and concentrated under reduced pressure. The residue was dissolved in ethanol (50 mL). To the solution was added 0.2N hydrochloric acid (50 mL). The resultant mixture was heated to 110° C. for 8 h, and cooled with an ice-water bath. The precipitate that formed was collected by filtration and washed with isopropanol to give the desired product. (5.5 g, 41%) LCMS: (M+H)=286.8/288.8. 1H-NMR (400 MHz, CDCl3): 8.60 (s, 1H), 7.79 (dd, J=8.6, 2.0 Hz, 1H), 7.68 (dd, J=8.3, 7.0 Hz, 1H), 7.61 (dd, J=8.3, 2.0 Hz, 1H), 5.43 (s, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:17]([C:16]2[CH:20]=[CH:21][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:18])=[CH:7][CH:6]=1
Reactant: ClCCOc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(OCCCl)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a stirred solution of 1-(2-chloroethoxy)benzene (48 g, 1.0 eq) in 400 mL CH2Cl2 at 0° C. was added dropwise a solution of 4-methoxybenzoyl chloride (62 g, 1.2 eq) and AlCl3 (49 g, 1.2 eq) in 400 mL CH2Cl2 while maintaining the temperature at 0° C. After the addition, the reaction was stirred at rt for 1 h. Then added ice water to quench the reaction and extracted with CH2Cl2. The extract was washed with brine, dried and evaporated in vacuo. Hexane (500 mL) was added to the residue, cooled to 0° C. and stirred for 30 min, then filtered and washed with cold hexane and dried to give the product as a white solid (85 g, 96%). 1H NMR (400 MHz, CDCl3) δ7.79 (dd, J=6.8 Hz, 2.0 Hz, 4H), 6.97 (dd, J=8.8 Hz, 2.0 Hz, 4H), 4.32 (t, J=6.0 Hz, 2H), 3.89 (s, 3H), 3.86 (t, J=6.0 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].O.[NH2:12][NH2:13]>O>[NH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:9]=2)[NH:13][N:12]=1
Reactant: N#Cc1cc(Br)ccc1F
Reactant: NN
Solvent: O
Product: Nc1n[nH]c2ccc(Br)cc12
Reaction time: 48 h
Yield: 91 %

Procedure:
A mixture of 5-bromo-2-fluorobenzonitrile (5.00 g, 25 mmol) and hydrazine hydrate (10 mL) was heated at reflux for two hours and then it was allowed to stand at room temperature for two days. The reaction was treated with water (50 mL) and the solids were collected by filtration to give 3-Amino-5-bromo-indazole as a white solid (4.82 g, 91%): mp 165-175° C.; MS [M+H]+ 212, 214.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C@H:10]2[CH2:9][C@@H:8]([C:6]3[O:7][NH:29][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:20][CH:21]=1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 65.5 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorobenzyl)piperidine-1-carboxylate (2.53 g, 6.92 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.277 g, 6.92 mmol) dissolved in water (2.000 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.424 mL, 6.92 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 2 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-35% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(4-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.516 g, 65.5%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 1.83-2.14 (m, 4H), 2.55-2.65 (m, 1H), 2.72-2.81 (m, 1H), 2.93-3.03 (m, 1H), 3.08-3.19 (m, 1H), 3.61 (s, 3H), 3.95-4.05 (m, 1H), 4.20-4.30 (m, 1H), 5.73 (s, 1H), 6.91-6.99 (m, 2H), 7.02-7.09 (m, 2H). MS m/z 335 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[CH:23]([NH2:25])[CH2:22][CH2:21]2>>[F:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[CH:23]([NH:25][C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=3)[N:3]=1)[CH2:22][CH2:21]2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: NC1CCc2cccc(F)c21
Product: Nc1ccc2nc(NC3CCc4cccc(F)c43)ccc2c1

Procedure:
Step C+D: The title compound was prepared in accordance with the general method described in example 2 from 2-chloro-6-nitro-quinoline and rac-7-fluoro-indan-1-ylamine; MS: m/e=294.3 (M+H+).
Reaction SMILES: OC1C=CC(/C=C/C[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=CC=1OC.[CH3:32][O:33][C:34]1[C:43]([O:44][CH3:45])=[C:42]([O:46][CH3:47])[CH:41]=[CH:40][C:35]=1[CH:36]=[CH:37][CH2:38]Br>>[O:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:14]2[CH2:15][CH2:16][N:11]([CH2:38][CH:37]=[CH:36][C:35]3[CH:40]=[CH:41][C:42]([O:46][CH3:47])=[C:43]([O:44][CH3:45])[C:34]=3[O:33][CH3:32])[CH2:12][CH2:13]2)=[CH:18][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(C=CCBr)c(OC)c1OC
Reactant: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Product: COc1ccc(C=CCN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)c(OC)c1OC

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and (2,3,4-trimethoxy)cinnamyl bromide to produce the above.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[C:17]([Cl:30])[CH:16]=2)[NH:7][N:6]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:30][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)c1
Reactant: CN1CCNCC1
Product: CN1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Yield: 16 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 12) and N-methylpiperazine to give the title compound in 16% yield; NMR Spectrum: 2.10 (s, 3H), 2.28 (br s, 4H), 2.50 (hidden by DMSO, 4H), 2.77 (t, 2H), 4.41 (t, 2H), 5.25 (s, 2H), 7.19 (t, 1H), 7.23 (d, 1H), 7.29-7.33 (m, 2H), 7.44-7.48 (m, 1H), 7.57 (d, 1H), 7.89-7.91 (m, 1H), 8.29 (s, 1H), 8.53 (br s, 1H); Mass Spectrum: 512 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH:10]=O.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CC#N>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]2[O:1][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10][C:3]=2[CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)c(C=O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc2cc(C=O)ccc2o1
Temperature: 90 °C

Procedure:
4-Hydroxyisophthalaldehyde (TCI America) (10.75 g, 71.6 mmol) in CH3CN (150 mL) was treated with K2CO3 (10.1 g, 1 eq.) and ethyl bromoacetate (8.0 mL, 1 eq.). The mixture was heated at 90° C. for 18 h, then cooled and concentrated under vacuum. The residue was partitioned between EtOAc and water. The organic layer was dried over sodium sulfate and concentrated under vacuum. The crude product was purified on the Combiflash system with a 220 g silica gel column, eluting with hexanes/EtOAc. The product was obtained as a white solid, 3.8 g. 1H NMR (CDCl3) 10.08 (s, 1H, CHO), 8.24 (m, 1H), 8.01 (m, 1H), 7.72 (d, 1H), 7.63 (m, 1H), 4.48 (q, 2H, OCH2), 1.44 (t, 3H, OCH2CH3); m/z 218.94 [M+H]+.
Reaction SMILES: Cl.I[CH:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[OH:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[ClH:16].[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[O:25][CH:14]([CH3:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCCCCCC(I)Cn1ccnc1
Reactant: COc1ccc(O)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OC(C)CCCCCCn2ccnc2)c(Cl)c1

Procedure:
Combine the product of step (b) (2.5 g) with 2-chloro-4-methoxyphenol (5.2 g) and potassium carbonate (10 g) in acetone (100 ml) and relux for 48 hours. Evaporate the solvent, extract the resultant residue with dichloromethane and purify on a silica gel column, eluting with 100% CH2Cl2 →10% CH3OH/CH2Cl2.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[N:7]([CH2:22][C@H:23]2[CH2:27][CH2:26][CH2:25][O:24]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:32])(=O)=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[N:6]([CH3:32])[N:7]([CH2:22][C@H:23]2[CH2:27][CH2:26][CH2:25][O:24]2)/[C:8](=[N:10]/[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1cc(C(C)(C)C)nn1C[C@H]1CCCO1
Reactant: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\cc(C(C)(C)C)n(C)n1C[C@H]1CCCO1
Yield: 54.9 %

Procedure:
A mixture of Example 45C (392 mg, 1.0 mmol) and dimethyl sulfate (0.38 mL, 4.0 mmol) in toluene (2 mL) was heated in a microwave at 130° C. for 1 hour. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, MeOH/Et3N (90:10) in EtOAc in 10-60% gradient) to yield 223 mg (55%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44 (s, 9H), 1.51-1.68 (m, 1H), 1.79-1.97 (m, 2H), 2.01-2.18 (m, 1H), 3.62-3.84 (m, 2H), 3.92 (s, 3H), 4.07-4.12 (s, 3H), 4.14-4.26 (m, 1H), 4.50-4.63 (m, 1H), 4.65-4.79 (m, 1H), 6.92-7.02 (m, 1H), 7.31 (d, J=8.82 Hz, 1H), 7.63-7.75 (m, 2H); MS (ESI) m/z 406 [M+H]+, 404 [M−H].
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:19]=[CH:18][N:17](COCC3C=CC=CC=3)[N:16]=2)[CH:12]=[CH:11][C:10]=1[N:29]1[S:33](=[O:35])(=[O:34])[NH:32][C:31](=[O:36])[CH2:30]1)C1C=CC=CC=1>CCO.O.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[CH:12]=[CH:11][C:10]=1[N:29]1[S:33](=[O:35])(=[O:34])[NH:32][C:31](=[O:36])[CH2:30]1
Reactant: O=C1CN(c2ccc(-c3ccn(COCc4ccccc4)n3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: O=C1CN(c2ccc(-c3cc[nH]n3)cc2O)S(=O)(=O)N1

Procedure:
A solution of 5-[2-benzyloxy-4-(1-benzyloxymethyl-1H-pyrazol-3-yl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one in 10 mL of EtOH/water (1:1) is hydrogenated over 10% Pd/C (15 mg) at 1 atm for 18 h. The catalyst is filtered and the filtrate evaporated. The residue is re-dissolved in EtOH/HOAc (3:1) and hydrogenated over 10% Pd/C for 18 h. The catalyst is filtered and the filtrate evaporated to give the title compound: (M−1)−=293.
Reaction SMILES: CC#N.[F:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.[Br:19]N1C(=O)CCC1=O.CCOC(C)=O>[Al]>[Br:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([F:4])[CH:6]=2)=[N:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccnc(-c2cccc(F)c2)c1
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(-c2cccc(F)c2)ncc1Br
Temperature: 55 °C
Reaction time: 8 h
Yield: 13.7 %

Procedure:
A MeCN (22 mL) solution of 2-(3-fluorophenyl)-4-methoxypyridine (2.21 g, 10.88 mmol) and N-bromosuccinimide (2.129 g, 11.96 mmol) in a 40-mL vial was wrapped in aluminum foil and stirred at 55° C. overnight. 22 h later, the reaction was cooled to rt, quenched with 1:1 sat. aq. NaHCO3:sat. aq. Na2S2O3 and extracted thrice with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a brown oil. Column chromatography (50 g Snap Ultra column, 15% to 100% EtOAc/hept) afforded 5-bromo-2-(3-fluorophenyl)-4-methoxypyridine (0.420 g, 1.489 mmol, 13.69% yield) as a white amorphous solid. m/z (ESI) 282.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]([OH:17])=O)=[CH:6]2.[NH2:18][C@@H:19]([CH2:28][S:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]([NH:18][C@@H:19]([CH2:28][S:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:17])=[CH:6]2
Reactant: O=C(O)c1cc2cc(CO)cc([N+](=O)[O-])c2[nH]1
Reactant: COc1ccc(CSC[C@H](N)COC(=O)C(C)(C)C)cc1
Product: COc1ccc(CSC[C@@H](COC(=O)C(C)(C)C)NC(=O)c2cc3cc(CO)cc([N+](=O)[O-])c3[nH]2)cc1

Procedure:
5-Hydroxymethyl-7-nitro-1H-indole-2-carboxylic acid prepared in Preparation 38 and 2,2-dimethyl-propionic acid (R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propyl ester prepared in Preparation 31 were reacted according to the same procedure as Step B of Preparation 40 to give the title compound.