Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:27])[CH:11]([CH2:17][C:18]2[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Cl>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:27])[CH:11]([CH2:17][C:18]2[O:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)o1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
To a solution of zinc chloride (3.35 g, 24.6 mmol) in diethyl ether (70 ml) was added sodium borohydride (1.86 g, 49.1 mmol) and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off. To the filtrate was added a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-((5-(trifluoromethyl)-2-furanyl)methyl)propionate (4.40 g, 12.3 mmol) in diethyl ether (30 ml) and the mixture was stirred at room temperature for 2 hrs. 1N Hydrochloric acid was added to the reaction solution under ice-cooling for quenching, water (100 ml) was further added, and the mixture as extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((5-(trifluoromethyl)-2-furanyl)methyl)propionate (3.46 g, 78%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][C:14]([S@:17]([NH-:19])=[O:18])([CH3:16])[CH3:15].[BH4-].[Na+]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:19][S@@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: CC(C)(C)[S@]([NH-])=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Product: COc1cc([C@@H](C)N[S@](=O)C(C)(C)C)ccc1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.4 %

Procedure:
To a THF (63 ml) solution of 1-(4-hydroxy-3-methoxyphenyl)ethanone (4.99 g, 30.0 mmol, purchased from TCI) and (R)-(+)-2-methyl-2-propanesulfinylamide (4.00 g, 33.0 mmol), titanium(IV) ethoxide (63.0 ml, 0.30 mol) was added under a nitrogen atmosphere and the mixture was refluxed with stirring for 20 hours. After imine formation was confirmed with LC-MS, the mixture was cooled to r.t. and the imine solution was added dropwise to a suspension of sodium borohydride (3.41 g, 90.1 mmol) in THF (50 mL) at 0° C. under nitrogene atmosphere. After stirring at room temperature for 3 hours, the reaction mixture was partitioned with water and ethanol, then the mixture was stirred for 1 hour at room temperature. The mixture was filtered through a Celite pad, and the filtrate was evaporated and concentrated in vacuo. The mixture was dissolved in EtOAc (500 ml), washed with 1N hydrochloric acid (300 ml), saturated aqueous sodium bicarbonate (300 ml), and brine (300 ml), and the organic layer was dried over sodium sulfate. Removal of the solvent gave a residue, which was chromatographed on a column of silica gel, eluting with EtOAc-hexane (1:1 to 3:1), to give the title compound (4.10 g, 50%) as a colorless syrup. 1H NMR (270 MHz, CDCl3) δ ppm 1.23 (9H, s), 1.49 (3H, d, J=6.6 Hz), 3.36 (1H, m), 3.89 (3H, s), 4.40-4.60 (1H, m), 5.71 (1H, s), 6.87 (3H, m).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:43])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:39])[NH:32][C:33]5[S:37][N:36]=[C:35]([CH3:38])[CH:34]=5)=[CH:27][C:26]=4[N+:40]([O-])=O)=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].C(O)C.O1CCCC1>O.C(OCC)(=O)C.[Fe]>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:43])[NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:39])[NH:32][C:33]5[S:37][N:36]=[C:35]([CH3:38])[CH:34]=5)=[CH:27][C:26]=4[NH2:40])=[CH:22][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)c([N+](=O)[O-])c2)sn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)c(N)c2)sn1
Temperature: 90 °C
Yield: 60.1 %

Procedure:
The product of Example 167A (200 mg, 0.328 mmol), ammonium chloride (115 mg, 2.152 mmol), and iron powder (113 mg, 2.021 mmol) in a mixture of water (2 mL), ethanol (4 mL) and tetrahydrofuran (4 mL) was heated at 90° C. under a nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with water (3×50 mL) and brine (50 mL). The organic was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Purification by silica gel chromatography eluting with 5% methanol/methylene chloride afforded the product as a gold-colored solid (114 mg, 60%).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1>O1CCCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([C:15]2[C:16]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: Brc1cccc2ccccc12
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: c1ccc2c(C3CC3)cccc2c1

Procedure:
Cyclopropylmagnesium bromide was added to a solution of bromonaphthalene in tetrahydrofuran stirred at 0-5° C. in the presence of catalytic amount of [1,3-bis(diphenylphosphino)propane]dichloronickel(II) to form cyclopropylnaphthalene, which was diluted with ethyl acetate and washed.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:8]=[CH:7][N:6]([C:9]2[N:10]=[CH:11][C:12]([O:23][CH3:24])=[C:13]3[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)=[CH:16][NH:15][C:14]=23)[N:5]=1)[CH3:3].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[C:32]2[CH2:40][CH2:39][NH:38][CH2:37][C:33]=2[N:34]=[CH:35][N:36]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CO>[OH:1][CH:2]([C:4]1[N:8]=[CH:7][N:6]([C:9]2[N:10]=[CH:11][C:12]([O:23][CH3:24])=[C:13]3[C:17]([C:18](=[O:22])[C:19]([N:38]4[CH2:39][CH2:40][C:32]5[C:31]([C:26]6[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=6)=[N:36][CH:35]=[N:34][C:33]=5[CH2:37]4)=[O:21])=[CH:16][NH:15][C:14]=23)[N:5]=1)[CH3:3]
Reactant: COc1cnc(-n2cnc(C(C)O)n2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: c1ccc(-c2ncnc3c2CCNC3)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(-n2cnc(C(C)O)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(ncnc4-c4ccccn4)C3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of 2-(7-(3-(1-hydroxyethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (18 mg, 0.054 mmol), 4-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (1.53 mg, 0.054 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (20.93 mg, 0.065 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.095 mL, 0.543 mmol). The mixture was stirred at room temperature for 2 hours, diluted with MeOH and purified by prep. HPLC to give 1-(7-(3-(1-hydroxyethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(pyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethane-1,2-dione (17 mg, 0.030 mmol, 54.8% yield). LCMS: m/z 526.2 (M+H)+, 1.54 min (method 8). 1H NMR (500 MHz, MeOD) d ppm 9.17 (s, 1H) 8.99-9.10 (m, 1H) 8.61-8.74 (m, 1H) 8.27-8.32 (m, 1H) 7.92-8.04 (m, 2H) 7.74-7.79 (m, 1H) 7.43-7.53 (m, 1H) 5.09 (q, J=6.41 Hz, 1H) 4.80-5.02 (m, 2H) 3.76-4.02 (m, 5H) 3.24-3.38 (m, 2H) 1.60-1.89 (m, 3H).
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C[Si]([N:28]=[C:29]=[O:30])(C)C>C(Cl)Cl>[N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:29]([NH2:28])=[O:30])[CH2:22][CH2:23]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Product: NC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
To a solution of cis-(octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (CC-033) (0.053 g, 0.16 mmol) in DCM (1 mL) was added trimethylsilylisocyanate (1.6 mmol). The mixture was stirred at room temperature overnight and then more trimethylsilylisocyanate (1.6 mmol) was added and the mixture stirred for a further 5 hours. The solution was diluted with DCM (10 mL) and washed with water. The resulting organic solution was dried and the solvent evaporated. The resulting oil was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.014 g). LCMS m/z 376.12 [M+H]+ RT=8.89 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.25 (s, 1H), 6.9 (s, 1H), 4.7 (s, 2H), 4.6 (m, 1H), 4.1 (m, 2H), 3.8 (m, 1H), 3.2-2.7 (m, 4H), 2.1-1.05 (m, 17H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH3:12])[CH2:5][C:6]2=[O:11].[Cu][C:14]#[N:15]>CN(C=O)C.O.Cl.C1(C)C=CC=CC=1.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[C:14]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH3:12])[CH2:5][C:6]2=[O:11])#[N:15]
Reactant: N#C[Cu]
Reactant: CC1CC(=O)c2cccc(Br)c21
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC1CC(=O)c2cccc(C#N)c21
Reaction time: 6 h

Procedure:
A mixture of 2.6 g (11.5 mmol) of 4-bromo-3-methyl-1-indanone [J. Org. Chem. 22, 1019 (1957)] and 1.14 g (12.7 mmol) of copper(I) cyanide in 2.5 ml of DMF is stirred for 6 hours at 170°. The reaction mixture is then cooled to 100°, and 50 ml of toluene and a solution of 4.5 g (16.5 mmol) of iron(III) chloride hexahydrate in 7 ml of water and 1.7 ml of concentrated hydrochloric acid are added in succession thereto. The reaction mixture is stirred for 20 minutes at 70°, cooled and diluted with toluene and water. The organic phase is separated off, washed with water, a semi-saturated sodium hydrogen carbonate solution and again with water, dried and concentrated by evaporation. The residue is distilled at 100°-120°/0.05 mbar in a bulb tube still and corresponds to starting compound (a), m.p. 109°-111°; IR (CH2Cl2): 2220, 1710 cm-1 ; 1H-NMR (CDCl3): δ=7.92 (m,2H); 7.52 (t,1H); 3.73 (m,1H); 3.03 (q,1H); 2.40 (q,1H); 1.55 (d,3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([F:27])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([O:19]C)[CH:13]=1)[CH:9]=[C:8]([C:21]([O:23]CC)=[O:22])[C:7]2=[O:26].Br>C(O)(=O)C>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([F:27])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([OH:19])[CH:13]=1)[CH:9]=[C:8]([C:21]([OH:23])=[O:22])[C:7]2=[O:26]
Reactant: CCOC(=O)c1cn(-c2ccc(F)c(OC)c2)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cn(-c2ccc(F)c(O)c2)c2c(Cl)c(F)c(F)cc2c1=O
Yield: 78.9 %

Procedure:
Ethyl 8-chloro-6,7-difluoro-1-(4-fluoro-3-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (2.3 g) was added to a mixed liquid (1:1, v/v; 20 ml) of 47% hydrobromic acid and acetic acid, and the mixture was stirred and heated under reflux for 78 hours. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (1.63 g) as a colorless powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([F:35])=[C:16]([C@:18]34[O:26][CH2:25][CH2:24][C@H:23]3[CH2:22][S:21][C:20]([NH:27]C(=O)OC(C)(C)C)=[N:19]4)[CH:17]=2)=[O:10])=[N:7][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][C:20]1[S:21][CH2:22][C@@H:23]2[CH2:24][CH2:25][O:26][C@:18]2([C:16]2[CH:17]=[C:12]([NH:11][C:9](=[O:10])[C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH:13]=[CH:14][C:15]=2[F:35])[N:19]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(C#N)cn4)ccc3F)OCC[C@H]2CS1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@@]34N=C(N)SC[C@@H]3CCO4)c2)nc1
Yield: 146.8 %

Procedure:
A solution of tert-butyl ((4aR,7aR)-7a-(5-(5-cyanopicolinamido)-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (6 mg, 0.012 mmol) and TFA (18.58 μL, 0.241 mmol) in DCM (121 μL) was stirred at rt for 3 h. The solvents were removed to give N-(3-((4aR,7aR)-2-amino-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-cyanopicolinamide (7 mg) as its TFA salt as a colorless oil. 1H NMR (500 MHz, CD3OD) δ 9.07 (1H, s), 8.46 (1H, dd, J=2.0, 8.0 Hz0, 8.37 (1H, d, J=8.0 Hz0, 8.17 (1H, dd, J=3.0, 7.5 Hz), 7.93 (1H, m), 7.25 (1H, dd, J=9.0, 11.0 Hz), 4.23 (2H, m), 3.43 (1H, m), 3.29 (1H, m), 3.15 (1H, m), and 2.31 (2H, m). MS (M+H)+: 398.1.
Reaction SMILES: [N:1]([CH2:4][CH:5]([CH2:29][C:30]#[N:31])[CH2:6][O:7][C:8](=[O:28])[NH: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][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N+]=[N-].C(OC(C)CC(COC(=O)NCCCCCCCCCCCCCCCCCC)CN)(=O)C1C=CC=CC=1>[Pd].CO>[C:30]([CH2:29][CH:5]([CH2:6][O:7][C:8](=[O:28])[NH: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][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][NH2:1])#[N:31]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CC#N)CN=[N+]=[N-]
Agent: [Pd]
Agent: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)CC(C)OC(=O)c1ccccc1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)CC#N

Procedure:
A mixture of 1-azido-2-cyanomethyl-3-octadecylcarbamoyloxypropane Vn2b, 80 mg of 10% palladium on charcoal in 40 ml of methanol is hydrogenated by the same procedure as described in (129) and crude product of the titled compound IVn2 is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH:10]=[O:11].[CH3:13][C:14]([CH3:17])([O-])[CH3:15].[K+].C(Cl)C(=C)C>CN(C=O)C>[CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH:9]([CH2:15][C:14]([CH3:17])=[CH2:13])[CH:10]=[O:11]
Reactant: CC(C)(C)[O-]
Reactant: CC1(C)C2CCC(CC=O)C1C2
Agent: C=C(C)CCl
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)CC(C=O)C1CCC2CC1C2(C)C
Yield: 29.6 %

Procedure:
In a manner similar to Example 6, 90 g of 6,6-dimethylbicyclo[3.1.1]hept-2-yl acetaldehyde (0.529 mole) in 40 ml of DMF, 108 g of potassium t-butoxide (0.91 mole) in 400 ml of DMF, and 93 g of methallyl chloride (1.02 moles) in 40 ml of DMF were reacted in the usual manner. After work-up the crude mixture of C- and O-alkylates, 112 g, was heated at 165°-175° C. for 4 hours. The crude product was dwastilled to afford 34.5 g of purified product (30% yield). BP 90° C./0.1 mmHg; 1H-NMR (300 MHz), δ 1.06 (3H, s), 1.16 s), 1.69 (3H, s), 1.3-2.6 (12H, m), 4.67 (1H, s), 4.74 (1H, s), 9.36 (1H, m); 13C-NMR (75 MHz), spectra consistent with assigned structures; IR (Neat) 2960, 2700, 1730, 1650, 1470, 1370, 890 cm-1 ; MS (m/e), 220 (M+), 205, 189, 177, 163, 149, 135, 121, 107, 93, 79, 69, 41 (Base);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]([CH2:19][CH3:20])[S:17][C:16](=[O:21])[NH:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:12])F.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29]O[CH2:27][CH2:26]1>>[N:25]1([CH2:30][CH2:29][N:15]2[N:14]=[C:13]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH2:10][F:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]([CH2:19][CH3:20])[S:17][C:16]2=[O:21])[CH2:26][CH2:27][CH2:23][CH2:24]1
Reactant: CCC1SC(=O)NN=C1c1ccc(OC(F)F)c(OC)c1
Reactant: ClCCN1CCOCC1
Product: CCC1SC(=O)N(CCN2CCCC2)N=C1c1ccc(OCF)c(OC)c1

Procedure:
of 5-(3-methoxy-4-difluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one with 1-chloro-2-morpholinoethane:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[N:18][CH:19]=[C:20](Cl)[N:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[N:18][CH:19]=[C:20]([C:31]4[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)[N:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3nc(Cl)cnc3o2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cc3nc(-c4ccc(S(C)(=O)=O)cc4)cnc3o2)CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-(2-chloro-furo[2,3-b]pyrazin-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (200 mg), 4-(methanesulfonyl)phenyl boronic acid (140 mg), Na2CO3 (126 mg), water (2.5 mL), and N,N-dimethylformamide (2.5 mL) is sparged with argon for 10 min and Pd(PPh3)4 (15 mg) is added. The resulting mixture is stirred at 100° C. for 1.5 h. After cooling to room temperature, water and ethyl acetate are added. The organic phase is washed with brine, dried (MgSO4), and the solvent is evaporated. The residue is chromatographed on silica gel (ethyl acetate/cyclohexane 60:40) to give an oily residue that is triturated with diethyl ether and dried to afford the title compound as a colorless solid. Yield: 175 mg (65% of theory); LC (method 2): tR=1.35 min; Mass spectrum (ESI+): m/z=458 [M+H]+.
Reaction SMILES: CN(C([O:8][N:9]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:55])[C:31]=1[NH:32][C:33]1[C:42]2[C:37](=[C:38]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([OH:53])=O)[C:39]([O:43][CH3:44])=[CH:40][CH:41]=2)[O:36][C:35](=[O:54])[CH:34]=1.C(N(CC)CC)C.NO.Cl>CS(C)=O>[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:55])[C:31]=1[NH:32][C:33]1[C:42]2[C:37](=[C:38]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([NH:9][OH:8])=[O:53])[C:39]([O:43][CH3:44])=[CH:40][CH:41]=2)[O:36][C:35](=[O:54])[CH:34]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC(=O)NO
Reaction time: 0.08 h

Procedure:
HATU (25 mg, 0.066 mmol) was added to a solution of 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanoic acid (25 mg, 0.053 mmol, Example 44), triethylamine (0.05 mL, 0.36 mmol), and DMSO (0.5 mL). After 5 min, NH2OH•HCl (10 mg, 0.14 mmol) was added. After an additional 17 h, the mixture was diluted with DMSO (1 mL), filtered through cotton, and the filtrate purified by reverse-phase HPLC (1:9→3:2; acetonitrile:water) to give 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)-N-hydroxyhexanamide: 1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.51 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.63 (s, 1H), 3.96 (t, 2H), 3.92 (s, 3H), 1.96 (t, 2H), 1.67 (m, 2H), 1.54 (m, 2H), 1.43 (m, 2H); MS (ESI): 481.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([NH2:11])[C:4]=1[NH2:12].CO[C:15]1C(OC)=C[C:18]2[NH:19][C:20](CCCNC)=N[C:17]=2[CH:16]=1>>[CH3:1][O:2][C:3]1[C:4]2[N:12]=[C:15]([CH2:16][CH2:17][CH2:18][NH:19][CH3:20])[NH:11][C:5]=2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(N)c(N)c(OC)c1
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Product: CNCCCc1nc2c(OC)cc(OC)cc2[nH]1

Procedure:
Prepared from 3,5-dimethoxy-benzene-1,2-diamine in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].O>CN(C)C(=O)C.C(Cl)Cl>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2F)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2F)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methyl propanoic acid (1.42 g 9.0 mmol) in N,N-dimethylacetamide (13 mL) was rapidly added thionyl chloride (1.13 g, 9.5 mmol) and the mixture (a precipitate formed after a few minutes) stirred at -15° to -5° C. for 1 hour. 4-(2-Fluorophenylsulfonyl)benzenamine (1.51 g, 6.0 mmol) was then added in one portion and the mixture allowed to stir at room temperature overnight. The solution was poured into water, the cloudy solution decanted from the resulting gum and filtered through a thin pad of Celite. The Celite pad was washed with methylene chloride and the solution added to a solution of the gum in methylene chloride. The combined methylene chloride solution was dried (MgSO4), filtered and the solvent removed in vacuo. The resulting gum was treated with hexane (100 mL) and enough methylene chloride (ca. 100 mL) to yield a solution. Methylene chloride was then boiled off on a steam bath at atmospheric pressure until cloudiness developed. The solution was cooled and scratched with a spatula until crystal growth began, returned to the steam bath and concentrated with swirling until the final volume was 100 mL. After cooling the solid was filtered to yield the title propanamide (1.92 g, 82%) as a light tan solid; mp 124°-133° C. 1H-NMR (400 MHz, d6 -DMSO): 1.59 (s, 3H, CH3), 7.41 (t, 1H, aromatic), 7.51 (t, 1H, aromatic), 7.59 (s, 1H, OH), 7.77 (m, 1H, aromatic), 7.85 (d, 2H, J=8.7 Hz, aromatic), 7.98-8.06 (m, 3H, aromatic), 10.48 (s, 1H, NH). MS (CI, CH4): 392(M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([NH2:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5].C([O-])(O)=O.[Na+].[C:21](=O)([O:30]N1C(=O)CCC1=O)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.O>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:11][C:12]([NH:15][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:13])[CH3:14]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(N)COc1cccc(N)c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(COc1cccc(N)c1C#N)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
To a solution of 2-amino-6-(2-amino-2-methylpropoxy)benzonitrile (Example 24d, 30.5 g, 148.6 mmol) in THF/H2O (1:1, 400 mL) was added NaHCO3 (24.7 g, 294 mmol), followed by benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (44.0 g, 176 mmol) at room temperature. The reaction was stirred at room temperature for 4 h then the organic layer was separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine and dried over MgSO4. After filtration, the solvent was evaporated and the crude oil was purified by chromatography on silica gel (eluent: 0-60% EtOAc in hexane) to give the title compound as yellow oil (44.8 g, 89%). 1H NMR (400 MHz, DMSO-d6) δ 1.30 (s, 6H), 4.02 (s, 2H), 4.96 (s, 2H), 5.98 (s, 2H), 6.14 (d, J=8.0 Hz, 1H), 6.32 (dd, J=0.8, 8.4 Hz, 1H), 7.12 (t, J=8.4 Hz, 1H), 7.38-7.21 (m, 6H). MS 340 (MH+).