Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7].[OH-].[Na+].[CH:16]1([CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][CH:30]3[O:32][CH2:31]3)=[CH:26][CH:25]=2)[CH2:18][CH2:17]1>C(O)C>[OH:32][CH:30]([CH2:29][O:28][C:27]1[CH:33]=[CH:34][C:24]([O:23][CH2:22][CH2:21][O:20][CH2:19][CH:16]2[CH2:18][CH2:17]2)=[CH:25][CH:26]=1)[CH2:31][NH:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7]
Reactant: c1cc(OCC2CO2)ccc1OCCOCC1CC1
Reactant: NCCNC(=O)N1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCCNCC(O)COc1ccc(OCCOCC2CC2)cc1)N1CCOCC1

Procedure:
26.2 g of the hydrochloride of N-2-aminoethyl-4-morpholinecarboxamide and 5.0 g of NaOH were refluxed in 175 ml of ethanol for 1 h. Thereafter 22 g of 3-(4-(2-cyclopropylmethoxyethoxy)phenoxy)-1,2-epoxypropane in 100 ml of ethanol was added and the resulting mixture refluxed for 16 h, filtered, and evaporated. The residue was dissolved in 300 ml of ethyl acetate and washed three times with water. The organic phase was then extracted with 250 ml of water at pH 5 (HCl). The aqueous phase was then made alkaline and extracted with methylene chloride. The methylene chloride phase was dried over Na2SO4, filtered, and evaporated. The residue was treated with ether and recrystallized from ethyl acetate. Yield 8.0 g. Melting point 80°-81° C. (base). The structure was determined using NMR-analysis.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:13]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:25][C:22]1[CH:23]=[CH:24][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[C:13]=2[CH:21]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1cccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1cccnc1
Yield: 67.1 %

Procedure:
A solution of [(S)-1-(6-fluoro-1-pyridin-3-yl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (292 mg, 0.82 mmol) in TFA (4 mL) and DCM (12 mL) was stirred for 1 h at RT. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PPC, gradient 0-10% 2M NH3 in MeOH/DCM) to afford the title compound as a pale yellow oil (141 mg, 67%). Marfey's test: 76% de. LCMS (Method C): RT 1.34 min [M+H]+ 257. 1H NMR (CDCl3, 400 MHz): δ 8.80 (1H, dd, J=5.0, 1.5 Hz), 8.73-8.72 (1H, m), 7.81 (1H, ddd, J=8.0, 2.5, 1.5 Hz), 7.71 (1H, ddd, J=9.0, 4.5, 0.5 Hz), 7.56 (1H, ddd, J=8.0, 5.0, 1.0 Hz), 7.04 (1H, ddd, J=9.5, 9.0, 2.5 Hz), 6.75 (1H, ddd, J=8.5, 2.5, 0.5 Hz), 4.08 (1H, q, 6.5 Hz), 1.87 (2H, bs), 1.48 (3H, d, J=6.5 Hz).
Reaction SMILES: [Li].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1.[CH3:18][C:19]([CH3:21])=[O:20].C(O)(=O)C>O1CCCC1>[CH3:18][C:19]([OH:20])([CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1)[CH3:21]
Reactant: CC(C)=O
Reactant: COc1cc(CCCBr)cc(OC)c1OC
Agent: [Li]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(CCCC(C)(C)O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 24.7 %

Procedure:
To anhydrous tetrahydrofuran (10 ml) stirred in an ice bath under nitrogen were added 104 mg (15 mmol) of lithium, 3.9 g (14 mmol) of 1-bromo-3-(3,4,5-trimethoxyphenyl)propane (1), and a solution of 0.95 ml (13 mmol) of acetone in tetrahydrofuran (10 ml). After the mixture was stirred for 17 hours at room temperature, a 2% aqueous solution of acetic acid (50 ml) chilled with ice was added to conduct extraction with diethyl ether. An organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil (4.1 g) was purified by column chromatography on silica gel, thereby obtaining 860 mg (yield: 24%) of 2-methyl-5-(3,4,5-trimethoxyphenyl)pentan-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.C([Li])(CC)C.Cl[C:27](=[O:42])[CH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1.O>C1COCC1>[Cl:1][C:2]1[C:3]([C:27](=[O:42])[CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:31][CH2:30]2)=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Cl)cnc21
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)Cl)CC1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)CC3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To a solution of 5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (0.338 g, 1.09 mmol, Adesis) in THF (5.5 mL) at about −78° C. was added sec-butyllithium (1.015 mL, 1.421 mmol) drop-wise. The reaction mixture was stirred at about −78° C. for about 1 h then a suspension of tert-butyl 4-(2-chloro-2-oxoethyl)piperidine-1-carboxylate (0.429 g, 1.64 mmol, Preparation #WWWW.1) in THF (2 mL) was added. The reaction mixture was stirred at about −78° C. for about 1 h then allowed to reach ambient temperature. Water (5 mL) was added and the product was extracted into DCM (3×10 mL). The combined organic extracts were washed with brine and dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-30% EtOAc in heptane to afford tert-butyl 4-(2-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxoethyl)piperidine-1-carboxylate (0.147 g, 25%) as a colorless oil: LC/MS (Table 1, Method r) Rt=3.97 min; MS m/z: 534/536 (M+H)+
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH:14]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[C:13]1=[O:30].[C:31](ON1C(=O)CCC1=O)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=1.C(N(CC)CC)C>C(Cl)Cl>[C:31]([NH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=1.[OH:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH:14]([N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])[C:13]1=[O:30]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(ON1C(=O)CCC1=O)c1cccnc1
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cccnc1)C(=O)O
Temperature: 25 °C

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-amino-3-methylbutanoate (200 mg) and 2,5-dioxopyrrolidinyl nicotinate (120 mg) were dissolved in DCM (20 mL). The mixture was stirred on a magnetic stirrer at room temperature. Triethylamine (1 mL) was added in one portion and the mixture was allowed to react overnight. The reaction mixture was then poured into DCM (30 mL), washed with saturated sodium bicarbonate solution three times (30 mL/wash) and brine (30 mL), dried with anhydrous magnesium sulfate, and filtered. The solvent was removed by rotary evaporation in vacuo. The crude product was purified by silica gel column chromatography (eluted with chloroform: acetone=5:2) to yield pure title compound (239 mg). 1HNMR (CDCl3, ppm) δ 9.04 (d, 1H, J=11.2Hz), 8.72 (s, 1H), 8.13 (d, 1H, J=8.0Hz), 7.87-7.90 (m, 2H), 7.76-7.78 (m, 2H), 7.41 (dd, 1H, J=8.0, 11.2Hz), 6.73 (d, 1H, J=9.6Hz), 5.86-5.98 (m, 2H), 5.05-5.08 (m, 1H), 3.00-3.15 (m, 1H), 2.80-2.95 (m, 2H), 2.12-2.28 (m, 1H), 2.10-2.20 (m, 2H), 0.97-1.05 (m, 3H), 0.85-0.88 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([OH:22])=[C:17]([F:23])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([OH:22])=[C:17]([F:23])[CH:16]=1)[C:7](=[O:12])[CH:6]=2
Reactant: Oc1cc2ccc(Br)cc2cn1
Reactant: Oc1c(F)cc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc2ccc(Br)cc2cn1Cc1cc(F)c(O)c(F)c1

Procedure:
The alkylation of 7-bromo-3-hydroxy-isoquinoline (1.30 g, 5.80 mmol) using 4-bromomethyl-2,6-difluorophenol (1.68 g, 7.54 mmol) and cesium carbonate (2.46 g, 7.54 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). The solid is collected by filtration, washed with water, ethyl acetate, and allowed to air dry under house vacuum. Drying will afford the desired product. Step (2): 2-(3,5-difluoro-4-hydroxybenzyl)-7-[3-(4H-[1,2,3]triazol-4-yl)prop-1-ynyl]-2H-isoquinolin-3-one
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCCCC.[F-:35].[K+]>>[F:35][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: [F-]
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [Cl-]
Product: O=[N+]([O-])c1cc(Cl)ccc1F
Yield: 72.3 %

Procedure:
2020 g (10.5 mol) of 2,5-dichloronitrobenzene, 70 g (0.2 mol) of octadecyltrimethylammonium chloride and 580 g (10.0 mol) of potassium fluoride were reacted analogously to Example 1. 936 g (72.3%, relative to 2,5-dichloronitrobenzene converted) of 2-fluoro-5-chloronitrobenzene and 600 g (29.7%, relative to 2,5-dichloronitrobenzene employed) of unreacted 2,5-dichloronitrobenzene were obtained.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24]C)[CH2:6][C:7]1[N:16]2[N:17]=[C:18]([NH2:20])[N:19]=[C:15]2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1.COC1C=C(C=C(OC)C=1)CC1N2N=C(N)N=C2C2C=CC=CC=2N=1>>[NH2:20][C:18]1[N:19]=[C:15]2[N:16]([C:7]([CH2:6][C:5]3[CH:4]=[C:3]([OH:2])[C:23]([OH:24])=[CH:22][CH:21]=3)=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)[N:17]=1
Reactant: COc1ccc(Cc2nc3ccccc3c3nc(N)nn23)cc1OC
Agent: COc1cc(Cc2nc3ccccc3c3nc(N)nn23)cc(OC)c1
Product: Nc1nc2c3ccccc3nc(Cc3ccc(O)c(O)c3)n2n1
Yield: 37 %

Procedure:
Operating as in Example 39, but employing 5-(3,4-dimethoxy-benzyl)-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine, prepared as described in Example 7, instead of 5-(3,5-dimethoxy-benzyl)-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine, the title compound was obtained in 37% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1.[NH2:16][C:17]([NH2:19])=[S:18]>>[CH3:1][O:2][C:3]([C:4]1[N:16]=[C:17]([NH2:19])[S:18][C:5]=1[C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1cccc(C)c1
Reactant: NC(N)=S
Product: COC(=O)c1nc(N)sc1-c1cccc(C)c1

Procedure:
prepared by reaction of 3-chloro-2-oxo-3-m-tolyl-propionic acid methyl ester with thiourea. LC-MS: tR=0.78 min; [M+H]+=249.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH:41]([C:43]2[CH:44]=[C:45](B(O)O)[C:46]([F:49])=[N:47][CH:48]=2)[CH3:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])(=O)C.[K+]>O1CCOCC1.ClCCl.O.[Cl-].[Na+].O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:45]3[CH:44]=[C:43]([CH:41]([N:38]4[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:34])[CH2:40][CH2:39]4)[CH3:42])[CH:48]=[N:47][C:46]=3[F:49])[N:3]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Reactant: CC(c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)n2)cc1
Temperature: 120 °C
Yield: 99.8 %

Procedure:
A glass microwave reaction vessel was charged with 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.140 g, 5.56 mmol) and 5-(1-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid (4.12 g, 11.68 mmol) in dioxane (25 mL). Then A-Phos (0.394 g, 0.556 mmol), potassium acetate (1.637 g, 16.68 mmol) and water (3 mL) were added into the reaction mixture. The reaction mixture was stirred and heated in a CEM Voyager Microwave (Large Scale Unit) at 120° C. for 20 min (160 watts, Powermax feature on). The mixture was diluted with dichloromethane (20 mL), water (20 mL) and brine solution (10 mL). The organic layer was collected by extracting with dichloromethane (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. This gave the crude product as a tan oil. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through silica-gel column (220 g), eluting with 100% ethyl acetate to give tert-butyl 4-(1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (3.65 g, 5.55 mmol, 99% yield) as a tan solid. 1H NMR (400 MHz, d6-DMSO) δ 8.47 (dd, J=9.39, 2.35 Hz, 1H) 8.31 (d, J=1.57 Hz, 1H) 7.26 (dd, J=8.61, 3.33 Hz, 4H) 6.90 (dd, J=12.42, 8.71 Hz, 4H) 4.78 (d, J=12.91 Hz, 4H) 3.74 (d, J=8.02 Hz, 6H) 3.70 (d, J=6.85Hz, 1H) 3.28 (d, J=6.06 Hz, 4H) 2.50-2.53 (m, 3H) 2.21-2.39 (m, 4H) 1.37 (d, J=1.76 Hz, H). m/z (ESI, +ve ion) 658.3 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]2[CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:46])[CH2:24][C:25]([C:28]3[C:33](=[O:34])[C:32]([CH3:35])=[C:31]([CH2:36][CH2:37][C:38]([O:40]CC=C)=[O:39])[C:30](=[O:44])[C:29]=3[CH3:45])([CH3:27])[CH3:26])=[O:15])[S:8][CH2:9][CH:4]2[NH:3]1.N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]=[C:2]1[NH:6][CH:5]2[CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:46])[CH2:24][C:25]([C:28]3[C:33](=[O:34])[C:32]([CH3:35])=[C:31]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])[C:30](=[O:44])[C:29]=3[CH3:45])([CH3:27])[CH3:26])=[O:15])[S:8][CH2:9][CH:4]2[NH:3]1
Reactant: C=CCOC(=O)CCC1=C(C)C(=O)C(C(C)(C)CC(=O)OCCCCCNC(=O)CCCCC2SCC3NC(=O)NC32)=C(C)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC1=C(CCC(=O)O)C(=O)C(C)=C(C(C)(C)CC(=O)OCCCCCNC(=O)CCCCC2SCC3NC(=O)NC32)C1=O
Yield: 36.5 %

Procedure:
To a solution of the compound L (34 mg, 53 μmol) in 4 mL of THF was added tetrakis(triphenylphosphine)palladium(0) (6 mg, 5.3 μmol) followed by morpholine (46 μL, 0.53 mmol). After evaporation of the solvent, the residue was purified by flash chromatography using a gradient solvent system 10% MeOH/CH2Cl2 to 100% MeOH to give 12 mg (40%) of the compound M as a yellow solid. 1H NMR 400 MHz (CDCl3) δ7.05 (s, 1H), 6.10 (s, 1H), 5.16 (s, 1H), 4.51 (dd, J=8 Hz, 4.5 Hz, 1H), 4.35 (dd, J=8 Hz, 4.5 Hz, 1H), 3.93 (t, J=7 Hz, 2H), 3.72 (t, J=5.4 Hz, 1H), 3.17 (m, 2H), 2.93 (s, 2H), 2.90 (m, 1H), 2.72 (m, 2H), 2.40 (t, J=8 Hz, 2H), 2.19 (t, J=7.5 Hz, 2H), 2.12 (s, 3H), 1.98 (s, 3H), 1.78-1.52 (br, 6H), 1.52-1.38 (br, 4H), 1.42 (s, 6H), 1.30 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][B:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[O:4][C:3]1([CH3:15])[CH3:14].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>ClCCl>[F:17][C:18]1[CH:23]=[C:22]([CH:21]=[CH:20][CH:19]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([B:5]2[O:4][C:3]([CH3:15])([CH3:14])[C:2]([CH3:16])([CH3:1])[O:6]2)=[CH:8][CH:9]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: OB(O)c1cccc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(Oc3cccc(F)c3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
Into a 250 mL, round-bottom flask, was placed a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5 g, 22.72 mmol, 1.00 equiv) in dichloromethane (100 mL), (3-fluorophenyl)boronic acid (3.5 g, 25.01 mmol, 1.10 equiv), Cu(AcO)2 (5 g), 4 A molecular sieves (15 g), and triethylamine (4.6 g). The resulting solution was stirred overnight at room temperature. The solids were filtered out and the filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:100-1:50) to give 1.8 g (25%) of 2-[4-(3-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[Al+3].[Cl-].[Cl-].[Cl-].[OH:15][C:16]([C:24]([F:27])([F:26])[F:25])([CH:20]=[C:21]([CH3:23])[CH3:22])[C:17]([OH:19])=[O:18].Cl>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:21]([CH3:23])([CH3:22])[CH2:20][C:16]([OH:15])([C:24]([F:25])([F:26])[F:27])[C:17]([OH:19])=[O:18])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: CC(C)=CC(O)(C(=O)O)C(F)(F)F
Reactant: Fc1ccc2c(c1)CCO2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(CC(O)(C(=O)O)C(F)(F)F)c1cc(F)cc2c1OCC2
Temperature: 0 °C

Procedure:
A solution of 0.07 mol 5-fluoro-2,3-dihydro-benzofurane in 21 ml of dichloromethane is cooled to 3° C. To this solution 0.1 mol of AlCl3 is added over a period of 30 minutes. After this addition 0.05 mol of 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid is added dropwise over 30 minutes. The mixture is stirred for at least 6 h under reflux conditions. After complete reaction the solution is poured on a mixture of ice (50 ml) and 1M HCl (10 ml) and stirred for at least 1 hour. The aqueous phase is extracted three times with 51 ml of ethylacetate. The combined organic phases are washed with water, saturated sodium chloride solution (brine) and dried over magnesiumsulfate. The solvent is evaporated under vacuum. The product may be recrystallized from n-heptane. As the title compound is yielded in highly pure form the recrystallization is not necessary. The title compound may be used directly to start the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([NH2:12])=[N:8][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:8]([CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[N:12]=3)[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc2c(N)n[nH]c2c1
Reactant: COc1ccc(C(=O)CBr)cc1
Product: COc1ccc(-c2cn3[nH]c4cc(OC)ccc4c3n2)cc1

Procedure:
Compound 7-methoxy-2-(4-methoxyphenyl)-5H-imidazo[1,2-b]indazole (W302) was prepared using the general procedure for cyclization between 6-methoxy-1H-indazol-3-amine (90 mg, 0.3 mmol) and 2-bromo-1-(4-methoxyphenyl)ethanone (72 mg, 0.31 mmol), as white solid (50 mg, 57%). 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1 HO, 7.85-7.81 (m, 3 H), 7.16-7.12 (m, 3 H), 6.99 (dd, J=8.8, 2.4 Hz, 1 H), 3.90 (s, 3 H), 3.84 (s, 3 H); MS (ESI) m/z 294 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:14]=[C:13]([C:23]([O:25]C)=O)[CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1>C1(N)CCCC1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)[N:14]=[C:13]([C:23]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:25])[CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Agent: NC1CCCC1
Product: O=C(NC1CCCC1)c1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Yield: 139 %

Procedure:
A solution of methyl 6-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-(cyclopentylamino)pyrimidine-4-carboxylate (45 mg, 0.097 mmol) in cyclopentylamine (1 mL) was heated at 85° C. in a sealed tube for 24 hours. The reaction mixture was cooled and the excess cyclopentylamine was removed in vacuo. The resulting residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 hexanes:ethyl acetate) provided 6-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-(cyclopentylamino)pyrimidine-4-carboxamide (35 mg, 70%). 1H NMR (CDCl3) δ 8.34 (d, 1H), 7.78 (br, 1H), 7.65 (m, 2H), 7.31–7.26 (m, 2H), 7.14 (t, 2H), 7.07 (d, 1H), 5.16 (br, 1H), 4.34–4.24 (m, 2H), 2.07–2.00 (m, 4H), 1.80–1.48 (m, 12H); MS m/z 519 (M+1). A portion of this material was treated with anhydrous hydrochloric acid in ether to provide a hydrochloride salt as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][S:18][C:17]2[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:16]1=2)=O)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].B.O1CCCC1>O1CCCC1.C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:15]1[CH2:20][CH2:19][S:18][C:17]2[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:16]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(=O)N1CCSc2ccc([N+](=O)[O-])cc21
Agent: B
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a stirred solution of tert-butyl 2-hydroxyethyl(2-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)-2-oxoethyl)carbamate (620 mg, 1.560 mmol) in tetrahydrofuran (5 mL) was added borane-tetrahydrofuran complex (1 M in tetrahydrofuran; 4.68 mL, 4.68 mmol), dropwise to avoid excessive bubbling. The mixture was then stirred at room temperature for 2 hours. The mixture was then quenched via the slow, dropwise addition of MeOH. The quenched reaction was then diluted with ethyl acetate and washed with saturated sodium carbonate (3×). The organic phase was dried, filtered, and concentrated giving a red oil (595 mg, 99%). 1H NMR (DMSO-d6) δ 7.59-7.44 (m, 1H), 7.38-7.32 (m, 1H), 7.22-7.13 (m, 1H), 4.74 (t, J=5.1 Hz, 1H), 3.69-3.62 (m, 2H), 3.61-3.39 (m, 6H), 3.29-3.17 (m, 2H), 3.15-3.04 (m, 2H), 1.31, 1.24 (2s, 9H); ESI-MS (m/z, %): 406 (M+Na, 55), 328 (40), 284 (100).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([O:23]CC)=[O:22].[OH-].[Li+]>C(O)C.O>[O:1]=[C:2]1[C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 80 °C

Procedure:
The product from Example 1D (1.70 g, 5.04 mmol) was dissolved in ethanol (40 mL). A solution of lithium hydroxide (1.20 g, 50.10 mmol) in water (10 mL) was added, and the reaction was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated, neutralized with 2 N HCl, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and then concentrated to give the title compound. MS (DCI+) m/z 310 (M+H)+.