Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:5][C@H:4]([N:6]2[C:10]3=[N:11][CH:12]=[CH:13][N:14]=[C:9]3[C:8]([CH3:16])([CH3:15])[C:7]2=[O:17])[CH2:3]1.[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH3:16][C:8]1([CH3:15])[C:9]2[C:10](=[N:11][CH:12]=[CH:13][N:14]=2)[N:6]([C@@H:4]2[CH2:5][C@H:2]([NH:1][C:27]([C:19]3[NH:18][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=3)=[O:28])[CH2:3]2)[C:7]1=[O:17]
Reactant: CC1(C)C(=O)N([C@H]2C[C@@H](N)C2)c2nccnc21
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)N([C@H]2C[C@@H](NC(=O)c3nc4ccccc4[nH]3)C2)c2nccnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 9.1 %

Procedure:
To a round bottomed flask was added 5-(cis-3-aminocyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (0.1518 g, 0.497 mmol), 1H-benzimidazole-2-carboxylic acid (0.097 g, 0.597 mmol, ChemBridge Corporation), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.246 g, 0.647 mmol, GenScript) and triethylamine (0.277 ml, 1.989 mmol, Sigma-Aldrich Chemical Company, Inc.) in DCM (1.658 ml) to stir at room temperature for 5 h. Solvent was evaporated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc in hexane. LCMS showed product was not isolated at ≧95%. The crude product was taken up in DCM and loaded onto an AccuBond SCX cartridge. The cartridge was rinsed with DCM followed by MeOH to remove impurities. The column was then rinsed with 2.0 ammonia in MeOH. The fractions were evaporated in vacuo. The residue was taken up in MeOH at which time a precipitate was noted to form. The round bottomed flask was placed in the freezer overnight. The solid was filtered from the filtrate and washed with cold MeOH to give the title compound (17.1 mg, 0.045 mmol, 9.13% yield). LCMS showed product peak at 1.757 min (m+1=377.0).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([CH2:15]I)[O:12][C:11](=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC[O:20][C:21]([CH3:23])=[O:22].O>CC(O)=O.CC([O-])=O.[Ag+]>[C:21]([O:22][CH2:15][C@@H:13]1[CH2:14][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][C:11](=[O:17])[O:12]1)(=[O:20])[CH3:23]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](CI)C1
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Yield: 92.6 %

Procedure:
To a solution of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(iodomethyl)-tetrahydropyran-2-one (40.00 g, 108.0 mmol) in AcOH (660 mL), AgOAc (20.03 g, 118.8 mmol) is added. The resultant mixture is then heated at 125° C. for 6 hours. The reaction mixture is filtered through diatomite filter medium (Celite®). The obtained filtrate is evaporated to afford the residue. To this residue, EtOAc (500 mL) and water (600 mL) are added. The organic layer is separated and the aqueous layer is washed again with EtOAc (5×150 mL). The combined organic layers are washed with water (4×300 mL), brine (5×300 mL) and dried over anhydrous MgSO4, filtered and concentrated under the reduced pressure to afford 30.28 g (92.6%) of ((2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxo-tetrahydro-2H-pyran-2-yl)methyl acetate as yellow oil (HPLC purity 98%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]([CH3:36])[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:11][C:10]([F:13])([F:12])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:33]2[CH2:34][CH2:35][CH:30]([N:29]([C:21]3[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:20]=3[F:19])[CH3:36])[CH2:31][CH2:32]2)=[CH:4][CH:5]=1)([OH:18])[C:14]([F:17])([F:16])[F:15]
Reactant: CN(c1ccc([N+](=O)[O-])cc1F)C1CCNCC1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(c1ccc([N+](=O)[O-])cc1F)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Yield: 124.3 %

Procedure:
2-(4-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (2.369 mmol, 1.141 mL, 798 mg), N-(2-fluoro-4-nitrophenyl)-N-methylpiperidin-4-amine (2.369 mmol, 600 mg) and potassium carbonate (7.11 mmol, 982 mg) were combined and stirred at 70° C. overnight in acetonitrile (50 mL). The reaction mixture was filtered and concentrated under vacuum. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate and concentrated under vacuum to give the intermediate 1,1,1,3,3,3-hexafluoro-2-(4-((4-((2-fluoro-4-nitrophenyl)(methyl)amino)piperidin-1-yl)methyl)phenyl)propan-2-ol (1.5 g).
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[Na+].P(=O)(O)(O)O.BrN1C(=O)CCC1=O.[N+]([O-])([O-])=O.[Ag+:44]>C(OCCCC)(=O)C.O>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Ag+:44]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Ag+]
Agent: O=C1CCC(=O)N1Br
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCCCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Reaction time: 0.25 h

Procedure:
10.6 g of behenic acid and 300 ml of distilled water were mixed at 90° C. for 15 minutes, 31.1 ml of a 1N aqueous solution of NaOH was added thereto over 15 minutes while vigorously stirring, the mixture was allowed to stand for 1 hour, and the temperature was then decreased to 30° C. 7 ml of a 1N aqueous solution of phosphoric acid was added, 0.13 g of N-bromosuccinimide (C-2) was added thereto while stirring more vigorously, and the previously prepared silver halide grains A were then added thereto so that the amount of silver halide became 2.5 moles. 25 ml of a 1N aqueous solution of silver nitrate was further added thereto continuously over 2 minutes, and the mixture was stirred as it was for 90 minutes. 37 g of a 1.2 wt % butyl acetate solution of polyvinyl acetate was added to the aqueous mixture above so as to form a floc dispersion, the water was then removed, the residue was washed with water twice and the water was removed, 20 g of a 2.5 wt % solution of polyvinyl butyral (Denki Kagaku Kogyo K.K., Denka Butyral #3000-K) in a mixture of butyl acetate and isopropyl alcohol at 1:2 was added while stirring, subsequently 7.8 g of polyvinyl butyral (Denki Kagaku Kogyo, Denka Butyral #4000-2) and 57 g of 2-butanone were added to the gel mixture of organic acid and silver halide so obtained and dispersed by a homogenizer to give a silver behenate emulsion (acicular particles having an average short diameter of 0.04 lam, an average long diameter of 1 μm and a variance coefficient of 30%).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[C:13]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)(=[O:17])[CH2:14][CH2:15][CH3:16].Cl.[NH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:13]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:24])=[CH:25][CH:26]=1)(=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: COC(=O)CCN
Reactant: CCCC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 55.9 %

Procedure:
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg, 0.801 mmol) was added to a solution of 4-butyrylbenzoic acid (154 mg, 0.801 mmol), methyl 3-aminopropanoate hydrochloride (90.8 mg, 0.881 mmol), 1-hydroxy-7-azabenzotriazole (109 mg, 0.801 mmol), and triethylamine (120 μL, 0.86 mmol) in dichloromethane (8.0 mL). The reaction was stirred at room temperature for 19 h. The reaction was diluted with dichloromethane and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography gave methyl 3-(4-butyrylbenzamido)propanoate (124.1 mg, 56%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=8.4 Hz, 2H), 7.83 (d, J=8.2 Hz, 2H), 6.89 (br. s., 1H), 3.69-3.77 (m, 5H), 2.95 (t, J=7.2 Hz, 2H), 2.66 (t, J=5.8 Hz, 2H), 1.71-1.82 (m, 2H), 1.00 (t, J=7.43 Hz, 3H. MS (M+1): 278.2.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[C:1]([O:12][CH2:18][CH3:19])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCO
Reactant: CCCCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCC(=O)OCC
Temperature: 20 °C
Reaction time: 4 h

Procedure:
n-Decanoic acid (17.2 g), 36N aqueous sulphuric acid solution (3 cc) and ethanol (300 cc) are heated to boiling for 4 hours. After being cooled to a temperature in the region of 20° C., the solution is concentrated to dryness at 50° C. under vacuum (20 mm Hg; 2.7 kPa), and the residue is then taken up with dichloromethane (200 cc). The organic phase is washed with saturated aqueous sodium bicarbonate solution (2×100 cc), separated off after settling has taken place, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). Ethyl n-decanoate (18 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: ClC1N=C(Cl)N=C(Cl)N=1.O[N:11]=[C:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.[OH2:23]>CN(C=O)C>[O:23]=[C:12]1[NH:11][CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CCOC(=O)C1CCC(=NO)CC1
Reactant: O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCNC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4,6-trichloro-1,3,5-triazine (21.7 g) in DMF (25 mL) was added dropwise ethyl 4-(hydroxyimino)cyclohexanecarboxylate (27.2 g) in DMF (220 mL) over 30 min. The mixture was stirred at room temperature overnight, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give ethyl 7-oxoazepane-4-carboxylate (2.40 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](O)=[O:31])=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:30](=[O:31])[CH2:29][O:28][C:27]5[CH:33]=[CH:34][C:24]([Cl:23])=[CH:25][CH:26]=5)[CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3c(N4CCNCC4)ncnc3s2)cc1
Reactant: O=C(O)COc1ccc(Cl)cc1
Product: O=C(COc1ccc(Cl)cc1)N1CCN(c2ncnc3sc(-c4ccc(F)cc4)nc23)CC1
Yield: 48 %

Procedure:
This compound was prepared from 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidine using 4-chlorophenoxyacetic acid in a yield of 48%, according to the procedure for the synthesis of example 50.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][O:8][C:7]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:6]1=2.[CH2:23]([O:25][C:26](=[O:39])[CH:27]([O:36][CH2:37][CH3:38])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[CH2:23]([O:25][C:26](=[O:39])[CH:27]([O:36][CH2:37][CH3:38])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:2][CH2:3][O:4][CH:5]2[C:12]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=3[O:10][CH2:9][O:8][C:7]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:6]2=3)=[CH:33][CH:34]=1)[CH3:24]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: Clc1ccc2c(c1)C(OCCBr)c1cc(Cl)ccc1OCO2
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCOC2c3cc(Cl)ccc3OCOc3ccc(Cl)cc32)cc1)OCC
Temperature: 60 °C
Yield: 52.9 %

Procedure:
To a solution of 12-(2-bromo-ethoxy)-2,10-dichloro-12H-5,7-dioxa-dibenzo[a,d]cyclooctene (404 mg, 1.0 mmol) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (238 mg, 1.0 mmol) in dry toluene (6 mL) was added potassium carbonate (276 mg, 2.0 mmol) and 18-crown-6 (528 mg, 2.0 mmol). The mixture was heated at 60° C. for 16 h. The mixture was filtered, and concentrated in vacuo. The residue was submitted to flash chromatography using toluene/ethyl acetate (19:1) as eluent to give 297 mg (53%) of the title compound; 1H NMR (300 MHz, CDCl3) δ1.18 (t, 3H), 1.25 (t, 3H), 2.96 (d, 2H), 3.30-3.42 (m, 1H), 3.55-3.65 (m, 1H), 3.90-3.95 (m, 2H), 4.0 (t, 1H), 4.15-4.25 (m, 4H), 4.55 (d, 1H), 5.87 (d, 1H), 6.18 (s, 1H), 6.88-6.95 (m, 4H), 7.10-7.25 (m, 4H), 7.60 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: NC1CCCC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
To a solution of 5.82 g (30 mmol) of 2,4-dichloro-5-nitropyrimidine (N. Whittaker, J. Chem. Soc., 1951:1565–1570) in 100 mL THF at −78° C. is added dropwise over 5 minutes a solution of 5.11 g (60 mmol) of cyclopentylamine in 20 mL THF. After a further 10 minutes at −78° C., the mixture is allowed to warm to room temperature, and the solvent is removed under vacuum. The residue is then extracted into EtOAc, washed with water, and dried with Na2SO4. Removal of the solvent and chromatography on SiO2, eluting with hexane/EtOAc (95:5) gives 6.20 g (85%) of the title compound: mp (hexane) 80–81.5° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[OH:32])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH2:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[CH:42]=[N:41][CH:40]=[CH:39]2>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH:20]2[O:32][CH2:35][C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[CH:42]=[N:41][CH:40]=[CH:39]3)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(O)C1
Reactant: BrCc1ccc2cnccc2c1
Agent: Br
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3cnccc3c2)C1

Procedure:
By alkylating tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxy-piperidine-1-carboxylate [Example 86 (n)] with 6-bromomethyl-isoquinoline hydrobromide (Example 4) analogously to Example 1 (g) there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(isoquinolin-6-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 583 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][C:5]2=[N:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Cl)cnc2C1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1cnc2n1CCNC2

Procedure:
1,1-Dimethylethyl 3-chloro-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (I19) (1.55 g, 6.01 mmol) and 4N HCl in 1,4-dioxane (6.01 mmol) was stirred at RT in 1,4-dioxane (5 mL) for 16 h. Solvents were removed in vacuo and the residue was loaded on to SCX (Varian 2×10 g) in methanol. The columns were washed with methanol and basic products eluted with 2M ammonia/methanol. The basic fractions were concentrated in vacuo to afford product in 913 mg that was used in subsequent steps without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=1)[CH3:2].[CH2:25]([N:32]1[CH2:39][CH2:38][NH:37][CH2:36][C:33]21[CH2:35][CH2:34]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([N:37]2[CH2:36][C:33]3([CH2:35][CH2:34]3)[N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:39][CH2:38]2)[CH:7]=1)[CH3:2]
Reactant: c1ccc(CN2CCNCC23CC3)cc1
Reactant: CCOC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc2ccccc12
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cc(N2CCN(Cc3ccccc3)C3(CC3)C2)cc2ccccc12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
(3-Trifluoromethanesulfonyloxy-naphthalen-1-yl)-acetic acid ethyl ester (500 mg, 1.38 mmol) is dissolved under an atmosphere of argon in dry THF (10 ml). 4-Benzyl-4,7diaza-spiro[2.5]octane (325 mg, 1.61 mmol) is added, followed by the addition of K3PO4 (410 mg, 1.93 mmol), Pd2(dba)3 (62 mg, 0.069 mmol) and biphenyl-2-yl-di-tert-butyl-phosphane (21 mg, 0.069 mmol). The reaction mixture is heated to 80° C. After 4 h, TLC analysis indicates complete consumption of starting materials. The reaction mixture is cooled to RT, filtered and concentrated. The residue is purified by FCC (hexanes/EtOAc 100:0 to 90;10 to 80:20 to 70:30 to 0:100) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 0.69 (ddd, 2H), 0.86 (ddd, 2H), 1.24 (t, J=7.0 Hz, 3H), 3.09 (ddd, 2H), 3.19 (s, 2H), 3.31 (ddd, 2H), 3.93 (s, 2H), 4.02 (s, 2H), 4.17 (q, J=7.0 Hz, 2H), 7.08 (s, 1H), 7.21 (s, 1H), 7.33 (m, 6H), 7.42 (dd, J=8.8 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H); ES-MS: 415 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8](=O)[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1.[BH4-].[Na+]>C1C=CC=CC=1>[CH2:8]([C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccco1
Reactant: Nc1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Nc1ncccc1Cc1ccco1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
A mixture of 20 g (0.213 mol) of 2-aminopyridine and 22.5 g (0.234 mol) of furfural in 400 ml of benzene was refluxed for 2 hours. The benzene was then evaporated off and the residue was taken up with 500 ml of methanol. The mixture was stirred in an ice bath whereupon 8.9 g (0.234 mol) of NaBH4 were added in small portions. The mixture was then stirred at ambient temperature for 5 hours. After the methanol had been evaporated off, the residue was extracted with ether to give 24.1 g of furfuryl aminopyridine having a boiling point of b.p. 0.1=98° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([C:22]1[CH:27]=[CH:26][C:25](OB(O)O)=[CH:24][CH:23]=1)[CH2:20][CH3:21].ClCCl>C(N(CC)CC)C>[CH2:19]([C:22]1[CH:27]=[CH:26][C:25]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:24][CH:23]=1)[CH2:20][CH3:21]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCCc1ccc(OB(O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Reaction time: 20 h
Yield: 69.4 %

Procedure:
To a mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g), 4-propylphenylboric acid (0.49 g), cupric acetate (0.27 g), MS 4A (0.8 g) and dichloromethane (15 ml) was added at room temperature triethylamine (1.04 ml), and the resulting mixture was stirred for 20 hours. The reaction mixture was filtered to remove an insoluble material and the filtrate was concentrated under reduced pressure. The residue was subjected to separation and purification using column chromatography (ethyl acetate:hexane 1:2) to obtain methyl 7-(4-propylphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g) as a light yellow, oily substance.
Reaction SMILES: C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[F:35][C:36]1[CH:37]=[C:38]([OH:42])[CH:39]=[CH:40][CH:41]=1.Cl[C:44]1[CH:49]=[CH:48][C:47]([C:50]2[C:59]3[C:54](=[CH:55][C:56]([S:60]([NH:63][C:64]4[CH:69]=[CH:68][N:67]=[CH:66][N:65]=4)(=[O:62])=[O:61])=[CH:57][CH:58]=3)[CH:53]=[CH:52][N:51]=2)=[C:46]([O:70][CH3:71])[CH:45]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>O1CCOCC1>[F:35][C:36]1[CH:37]=[C:38]([CH:39]=[CH:40][CH:41]=1)[O:42][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[C:59]3[C:54](=[CH:55][C:56]([S:60]([NH:63][C:64]4[CH:69]=[CH:68][N:67]=[CH:66][N:65]=4)(=[O:61])=[O:62])=[CH:57][CH:58]=3)[CH:53]=[CH:52][N:51]=2)=[C:46]([O:70][CH3:71])[CH:45]=1
Reactant: Oc1cccc(F)c1
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(Oc2cccc(F)c2)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 165 °C
Reaction time: 0.17 h
Yield: 8.5 %

Procedure:
A microwave vial charged with di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine (0.034 g, 0.070 mmol), 3-fluorophenol (0.079 g, 0.703 mmol), 1-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.150 g, 0.351 mmol), potassium phosphate (0.298 g, 1.406 mmol), and 1.5 mL dioxane was heated to 165° C. in the microwave for 30 minutes. LC/MS showed product, so the reaction mixture was filtered through a 0.45 μm syringe filter and was treated with HCl (4N in dioxane) (0.351 ml, 1.406 mmol). After stirring for 10 minutes, the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [RediSep Gold C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(4-(3-fluorophenoxy)-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.015 g, 0.030 mmol, 8.49% yield). 1H NMR (MeCN-d3) δ: 8.69 (d, J=5.7 Hz, 1H), 8.62 (s, 1H), 8.48 (s, 1H), 8.22 (d, J=6.3 Hz, 1H), 7.89-7.97 (m, 2H), 7.80-7.88 (m, 1H), 7.38-7.47 (m, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.08 (d, J=5.9 Hz, 1H), 6.87-6.99 (m, 4H), 6.76 (d, J=8.3 Hz, 1H), 3.59-3.62 (m, 3H); (M+H)+=503.0.
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]([O:20][CH2:21][CH3:22])[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]1=[O:19])C.[NH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]2[C:30]([NH2:33])=[N:31][O:32][C:28]=2[CH:27]=1>>[NH2:33][C:30]1[C:29]2[CH:34]=[CH:35][C:26]([CH2:25][NH:24][C:4](=[O:23])[CH:5]([O:20][CH2:21][CH3:22])[N:6]3[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:7]3=[O:19])=[CH:27][C:28]=2[O:32][N:31]=1
Reactant: CCOC(=O)C(OCC)n1cccc(Nc2ccccc2)c1=O
Reactant: NCc1ccc2c(N)noc2c1
Product: CCOC(C(=O)NCc1ccc2c(N)noc2c1)n1cccc(Nc2ccccc2)c1=O

Procedure:
Using similar procedures as described in example 25, (RS)-ethoxy-(2-oxo-3-phenylamino-2H-pyridin-1-yl)-acetic acid ethyl ester (example 21.1) was hydrolyzed according to general procedure B. The corresponding acid was reacted according to general procedure C with 6-aminomethyl-benzo[d]isoxazol-3-ylamine (CAS 368426-78-2) to give (RS)-N-(3-amino-benzo[d]isoxazol-6-ylmethyl)-2-ethoxy-2-(2-oxo-3-phenylamino-2H-pyridin-1-yl)-acetamide. Light green powder. MS 434.2 ([M+H]+)