Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[C:4]([OH:19])[CH:3]=1.CC(C)=O.C(=O)([O-])[O-].[K+].[K+].[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>O>[N:30]1([C:36]([O:19][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=2[O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1OC(=O)N1CCOCC1
Yield: 99.2 %

Procedure:
To 19.0 g (68.8 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol were added 51.3 g of acetone and 10.5 g (75.7 mmol) of potassium carbonate, and the resultant mixture was stirred at 30° C. To the mixture was added dropwise 11.3 g (75.7 mmol) of morpholinecarbonyl chloride over one hour. The reaction mixture was subjected to reaction at 30° C. for 5 hours. After completion of the reaction, pure water was added to the reaction mixture to deposit solids, and then the solids were taken out by filtration. The resultant solids were dried under a reduced pressure, and the solids were quantitatively determined by an HPLC internal standard analysis method, which showed that 26.6 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl morpholine-4-carboxylate (yield: 99%) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH2:15][CH2:16][CH2:17][C:4]=2[N:3]=1.[CH3:18][O:19][C:20]([C:22]1([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23]1)=[O:21].CCOCC>C(O)CCC>[CH3:18][O:19][C:20]([C:22]1([C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:2]3[N:7]=[C:6]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:5]4[CH2:15][CH2:16][CH2:17][C:4]=4[N:3]=3)=[CH:30][CH:31]=2)[CH2:23][CH2:24][CH2:25]1)=[O:21]
Reactant: Clc1nc2c(c(Oc3ccccc3)n1)CCC2
Reactant: COC(=O)C1(c2ccc(N)cc2)CCC1
Solvent: CCCCO
Solvent: CCOCC
Product: COC(=O)C1(c2ccc(Nc3nc4c(c(Oc5ccccc5)n3)CCC4)cc2)CCC1
Temperature: 27.5 °C
Reaction time: 12 h
Yield: 83.1 %

Procedure:
A mixture of 2-chloro-4-phenoxy-6,7-dihydro-5H-cyclopentapyrimidine (0.28 g, 1.1 mmol) and 1-(4-amino-phenyl)cyclobutanecarboxylic acid methyl ester (0.23 g, 1.11 mmol) in 1-butanol (3.0 mL) was stirred at a temperature in the range of 20° C. to 100° C. for 8 to 16 hours. Thereafter, the reaction was cooled to about 20 to 35° C. Anhydrous ether was added and the mixture was stirred for 1 hour at about 20 to 35° C. The separated solid was filtered, washed with ether, and dried in vacuum to afford the title compound as a white solid (0.38 g, 81% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][CH:13]1[CH2:18][NH:17][C:16](=O)[CH2:15][N:14]1[C:20]([O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Br:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[N:17]3[CH2:18][CH:13]([CH3:12])[N:14]([C:20]([O:22][CH2:23][CH:24]4[C:36]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[C:30]5[C:25]4=[CH:26][CH:27]=[CH:28][CH:29]=5)=[O:21])[CH2:15][C:16]3=[N:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: CC1CNC(=O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1Cn2c(nc3cc(Br)ccc3c2=O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 2-amino-4-bromobenzoic acid (2.8 g, 13.1 mmol, 1.1 equiv), (9H-fluoren-9-yl)methyl 2-methyl-5-oxopiperazine-1-carboxylate (4 g, 11.9 mmol, 1 equiv), and phosphoryl trichloride (4 mL) in 1,4-dioxane (100 mL) was stirred at 80° C. for two hours. After it was cooled to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([CH3:16])([S:7]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)(=[O:9])=[O:8])[CH3:6])C.[OH-].[Na+]>O1CCOCC1.O>[CH3:16][C:5]([S:7]([CH:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)(=[O:8])=[O:9])([CH3:6])[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)C1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C(=O)O)S(=O)(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 82.6 %

Procedure:
To a solution of 166 g (0.63 mol) of 2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionic acid ethyl ester in THF/water (4/1, 1.66 L) are added 50.5 g (1.26 mol) of NaOH pellets in portions over 20 min. The reaction is stirred at room temperature for 2.5 d. The organic solvent is removed under reduced pressure and the aqueous residue is diluted with water (2 L) and washed with DCM (2 L). The aqueous layer is acidified to pH 1-2 with concentrated HCl and then extracted with DCM (3×2 L). The acidic aqueous is further saturated with NaCl and extracted again with DCM (6×2 L). The combined organic extracts are concentrated under reduced pressure to give 123 g of 2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionic acid as a white solid. Yield: 83%, ES-MS: m/z 235 [M−H]
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([NH2:23])[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]1[N:17]=[C:18]([NH2:23])[N:19]=[C:20]([NH:29][C:28]2[CH:30]=[CH:31][C:25]([Cl:24])=[CH:26][CH:27]=2)[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)cc(-c2cc(Cl)ccc2OCc2ccccc2)n1
Reactant: Nc1ccc(Cl)cc1
Product: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2cc(Cl)ccc2OCc2ccccc2)n1
Yield: 98 %

Procedure:
Following the method described in Example 72, 4-(2-benzyloxy-5-chloro-phenyl)-6-chloro-pyrimidin-2-ylamine and 4-chloro-aniline provided the title compound (98% yield). 1H NMR (CD3OD) δ 5.26 (s, 2H, CH2), 6.44 (s, 1H, Ar), 7.21 (d, 1H, J=8.8 Hz, Ar), 7.33-7.36 (m, 2H, Ar), 7.38-7.43 (m, 4H, Ar), 7.45 (d, 1H, J=8.8 Hz, Ar), 7.58-7.61 (m, 2H, Ar), 7.80-7.82 (m, 2H, Ar).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>O.[OH-].[Na+]>[N+:17]([C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[C:4](=[O:9])[NH:5][CH:6]=1)([O-:19])=[O:18]
Reactant: O=c1[nH]cccc1C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(trifluoromethyl)pyridin-2(1H)-one 2 (2.00 g, 12.26 mmol) and sulfuric acid (H2SO4, 3.5 ml, 30%) was heated to 90° C. and nitric acid (HNO3, 2.5 ml, 65%) was added. The mixture was stirred at 90° C. for 8 hours and additional nitric acid (1 ml, 65%) was added. The mixture was stirred for an additional 6 hours at 90° C. and was then poured into a beaker containing ice (30 ml). The mixture was diluted with water (30 ml) and 6N aqueous NaOH was added until a pH of about 4 to about 5. The mixture was extracted with ethyl acetate (3×40 ml), the combined organic phases dried over Na2SO4 and all solvents were removed under reduced pressure. The residue was dissolved in ethyl acetate and the product precipitated by the addition of hexane. After filtration, 5-nitro-3-(trifluoromethyl)pyridin-2(1H)-one 3 was obtained as a yellow powder (1.58 g, 7.59 mmol, 62%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1csc(C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1csc(CBr)n1
Yield: 44.8 %

Procedure:
A solution of ethyl 2-methylthiazole-4-carboxylate (5.0 g, 29 mmol), N-bromosuccinimide (6.2 g, 35 mmol) and azo-bis-(isobutyronitrile) (480 mg, 2.9 mmol) in carbon tetrachloride (150 ml) was heated at reflux for 18 h. The mixture was filtered and reduced. Chromatography (20% EtOAc/80% hexanes and 30% EtOAc/70% hexanes) afforded ethyl 2-bromomethylthiazole-4-carboxylate (3.25 g, 44%).
Reaction SMILES: [CH:1]1([N:4]([C:6]2[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=2[OH:14])[CH3:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:24][C:25](=[O:27])[CH3:26]>CC(C)=O>[CH:1]1([N:4]([C:6]2[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=2[O:14][CH2:24][C:25](=[O:27])[CH3:26])[CH3:5])[CH2:2][CH2:3]1
Reactant: CC(=O)CCl
Reactant: CN(c1cc(F)c(F)cc1O)C1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1cc(F)c(F)cc1N(C)C1CC1

Procedure:
53 mg of 2-(N-cyclopropyl-N-methylamino)-4,5-difluorophenol, 44 mg of potassium carbonate, 6.4 mg of potassium iodide and 0.03 ml of chloroacetone are mixed in 1 ml of acetone and are heated at reflux for 20 h. The mixture is then evaporated and the residue is taken up in diethyl ether and washed with water. The organic phase is dried with magnesium sulfate and evaporated to dryness, and the residue is purified by flash chromatography. 1-[2-(N-Cyclopropyl-N-methylamino)-4,5-difluorophenoxy]propan-2-one is thus obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]([N:6]2[CH2:37][CH2:36][C:9]([CH3:38])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]4[CH:18]=[CH:19][C:20]([F:34])=[CH:21][C:22]=4[C:23]4[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=4)[CH2:8][CH2:7]2)=[C:4]([C@H:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:40]([O:42][CH3:43])=[O:41])[C:3]=1[CH3:49].C(O[C@@H](C1C(C)=C(C2C=CN=CC=2)C2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)O[C:73]2[CH:74]=[CH:75][C:76]([F:99])=[CH:77][C:78]=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:45]([O:44][C@@H:39]([C:4]1[C:3]([CH3:49])=[C:2]([C:73]2[CH:78]=[CH:77][C:76]([F:99])=[CH:75][CH:74]=2)[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]=1[N:6]1[CH2:37][CH2:36][C:9]([CH3:38])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]2[CH:22]=[CH:21][C:20]([F:34])=[CH:19][C:18]=2[C:25]2[CH:26]=[C:27]3[CH:33]=[CH:23][CH:24]=2)[CH2:8][CH2:7]1)[C:40]([O:42][CH3:43])=[O:41])([CH3:46])([CH3:47])[CH3:48]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(-c2ccncc2)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(-c2ccc(F)cc2)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Yield: 66.7 %

Procedure:
Prepared in 66.7% yield from methyl(2S)-2-[(22S)-5-bromo-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate following the procedure for Methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,22,28-trimethyl-5-(pyridin-4-yl)-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 752.4.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:5]=1[CH:6]=O)[CH3:2].[C:18]([NH:22][OH:23])([CH3:21])([CH3:20])[CH3:19]>>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:5]=1[CH:6]=[N+:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[O-:23])[CH3:2]
Reactant: CCOc1cc(OCC)c(C=O)c(OCC)c1
Reactant: CC(C)(C)NO
Product: CCOc1cc(OCC)c(C=[N+]([O-])C(C)(C)C)c(OCC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 2,4,6-triethoxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 92.3% yield as a solid, m.p. 109.1° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH2:22][OH:23].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.O.C(Cl)Cl>[CH3:30][S:31]([O:23][CH2:22][C@@H:7]1[C@H:8]([NH:11][C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:21])[C:9](=[O:10])[N:6]1[CH2:5][C:4]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:3]=1[O:2][CH3:1])(=[O:33])=[O:32]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CO)c(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2COS(C)(=O)=O)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl ((2S,3S)-1-(2,4-dimethoxybenzyl)-2-(hydroxymethyl)-4-oxoazetidin-3-yl)carbamate (5.37 g, 13.41 mmol) and TEA (3.72 mL, 26.8 mmol) in DCM at 0° C. was added MsCl (1.15 mL, 14.75 mmol). After stirring at 0° C. for 1 h, it was diluted with water/DCM and the layers were separated. The aqueous layer was extracted with DCM (2×) and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was taken up in toluene and concentrated (2×), affording the title compound as an off white solid. It was used as such in subsequent reactions. LCMS: Rt=0.86 min, m/z=479.2 (M+1) Method 2m_acidic.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN([CH:28]=[O:29])C>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:28]=[O:29])[CH:16]=2)[O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCOc2ccc(Br)cc21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCOc2ccc(C=O)cc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(6-Bromo-chroman-4-yl)-carbamic acid tert-butyl ester (3.859 g, 11.76 mmol) was dissolved in THF (50 mL) and cooled to −78° C. n-Butyllithium (2.5 M) (11.76 mL, 29.40 mmol) was added drop-wise to the stirred solution. The reaction mixture was stirred at −78° C. for 30 min and DMF (4.55 mL, 58.8 mmol) was added drop-wise and the system was slowly warmed to RT overnight. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organics were dried with MgSO4 and concentrated in vacuo to afford the crude compound, which was purified by flash column chromatography to furnish the pure title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:12]=1[CH2:13][N:14]=[N+]=[N-])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:12]=1[CH2:13][NH2:14])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1CN

Procedure:
To a stirred solution 2-(1-tert-butyloxycarbonylaminoethyl)-5-chlorobenzylazide from the previous step (0.28 g, 0.90 mmol) in THF (10.0 mL) and water (1 mL) at ambient temperature was added Ph3P (0.29 mg, 1.1 mmol). The mixture was refluxed for 3 h. The reaction was partitioned between Et2O and diluted 1N HCl. The Et2O layer was removed, and the aqueous layer basicified with saturated NaHCO3 solution. The aqueous layer was extracted with Et2O which was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure. 2-(1-(tert-butyloxycarbonylamino)ethyl)-5-chlorobenzylamine was obtained as a pink oil (0.205 g; HPLC RT=2.76 min, method A; 1H NMR, 400 MHz, CDCl3, 7.33 ppm (s, 1H), 7.22 ppm (dd, 2H), 5.2 ppm (br s, 1H), 5.0 ppm (br s, 1H), 4.0 ppm (d, 1H), 3.85 ppm (d, 1H), 1.7 (br s, 1H), 1.4 ppm (s, 12H)).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][C:10](=[S:12])[NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15](=O)/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19]>C(O)C>[CH2:9]([C:10]1[S:12][CH:14]=[C:15](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])[N:11]=1)[CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)/C=C/C(=O)CBr
Reactant: NC(=S)C/C=C/c1ccccc1
Solvent: CCO
Product: O=C(O)/C=C/c1csc(CC=Cc2ccccc2)n1
Reaction time: 1 h
Yield: 48.8 %

Procedure:
(E)-4-phenylbut-3-enethioamide (120 mg, 0.68 mmol) was dissolved in ethanol (20 mL). (E)-5-bromo-4-oxopent-2-enoic acid (290 mg, 1.50 mmol) was then added at room temperature and the reaction mixture was stirred for 1 h. The solution was concentrated and the crude residue was purified by column chromatography to give (E)-3-(2-cinnamylthiazol-4-yl)acrylic acid (90 mg). ES+ (M+H)+ 272.
Reaction SMILES: [CH:1]([N:4]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=1)[CH2:5][C:6]1[N:7](COCC[Si](C)(C)C)[CH:8]=[N:9][CH:10]=1)([CH3:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>C(O)C.[Pd].O1CCCC1>[N:9]1[CH:10]=[C:6]([CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[C:19]2[CH:20]=[C:21]([NH:25][C:28](=[O:30])[CH3:29])[CH:22]=[CH:23][CH:24]=2)[NH:7][CH:8]=1
Reactant: CC(C)N(Cc1cncn1COCC[Si](C)(C)C)c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(N(Cc2cnc[nH]2)C(C)C)c1
Reaction time: 8 h

Procedure:
Isopropyl-(3-nitro-phenyl)-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-ylmethyl]-amine (0.055 g, 0.14 mmol) was dissolved in ethanol, palladium on charcoal (20 mg, 10% Pd) was added and the mixture was hydrogenated overnight. The catalyst was filtered off and the solvent was evaporated. The residue was dissolved in ethyl acetate and filtered over silica gel. After evaporation the residue was dissolved in toluene (1.5 ml) and tetrahydrofuran (3 ml), acetic anhydride (0.015 mg, 0.14 mmol) was added and the mixture was stirred overnight. The solvents were evaporated and the residue was partitioned between sodium bicarbonate solution and ethyl acetate. The organic layer was dried over magnesium sulphate and evaporated. The residue was dissolved in tetrahydrofuran (5 ml) and tetrabutylammonium fluoride solution (0.3 ml, 1M) in tetrahydrofuran was added. After stirring the mixture at 65° C. overnight the solvent was evaporated and the residue was purified by flash chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/methanol=95:5) to yield a white gum, (0.005 g, 34%); MS (ISP): 273.2 ((M+H)+.).
Reaction SMILES: P(OC1C=CC=CC=1)(OC1C=CC=CC=1)(O[C:4]1[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15](OC(F)(F)F)=[CH:14][CH:13]=2)[C:6](=[O:10])[CH2:7][CH2:8][CH:9]=1)=O.[F:37][C:38]([F:50])([F:49])[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O>>[F:37][C:38]([F:50])([F:49])[O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:4][N:5]2[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[O:39][C:38]([F:50])([F:49])[F:37])[CH2:9][CH2:8][CH2:7][C:6]2=[O:10])=[CH:42][CH:41]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: O=C1CCC=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)N1Cc1ccc(OC(F)(F)F)cc1
Product: O=C1CCCC(c2ccccc2OC(F)(F)F)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 9 (GP9) with 6-oxo-1-(4-(trifluoromethoxy)benzyl)-1,4,5,6-tetrahydropyridin-2-yl diphenyl phosphate and commercially available (2-(trifluoromethoxy)phenyl)boronic acid. Subsequent hydrogenation and purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.83 min.; [M+H]+: 433.70 g/mol.
Reaction SMILES: F[B-](F)(F)F.[F:6][C:7]1[C:12]2[CH2:13][O:14][CH2:15][O:16][C:11]=2[C:10]([O:17][CH3:18])=[CH:9][C:8]=1[CH:19]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=S)[NH2:42])=[CH:37][CH:36]=1)[C:20]1[NH:24][C:23](=[O:25])[N:22]([C:26]2[N:27]=[CH:28][S:29][C:30]=2[C:31]([NH2:33])=[O:32])[N:21]=1.C(O)(C)C.C[SiH](C)[NH:50][SiH](C)C>C(#N)C>[C:41]([C:38]1[CH:37]=[CH:36][C:35]([NH:34][CH:19]([C:8]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]3[O:16][CH2:15][O:14][CH2:13][C:12]=3[C:7]=2[F:6])[C:20]2[NH:24][C:23](=[O:25])[N:22]([C:26]3[N:27]=[CH:28][S:29][C:30]=3[C:31]([NH2:33])=[O:32])[N:21]=2)=[CH:40][CH:39]=1)(=[NH:42])[NH2:50]
Reactant: C[SiH](C)N[SiH](C)C
Reactant: COc1cc(C(Nc2ccc(C(N)=S)cc2)c2nn(-c3ncsc3C(N)=O)c(=O)[nH]2)c(F)c2c1OCOC2
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CC(C)O
Product: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncsc3C(N)=O)c(=O)[nH]2)c(F)c2c1OCOC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After adding 33 mg of Me3O+BF4− to a suspension of 109 mg of 4-{3-[(5-fluoro-8-methoxy-4H-benzo[1,3]dioxin-6-yl)-(4-thiocarbamoylphenylamino)methyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}thiazole-5-carboxylic acid amide in 1 ml of acetonitrile, the mixture was stirred at room temperature for 30 minutes. Next, 4 ml of isopropanol and 0.055 ml of 1,1,3,3-tetramethyldisilazane were added to the reaction mixture, which was then stirred overnight at 60° C. The reaction mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 4-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-4H-benzo[1,3]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}thiazole-5-carboxylic acid amide (36 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[NH:15][N:14]=[N:13][C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.[H-].[Na+].Br[CH2:19][C:20]1[CH:35]=[CH:34][C:23]2[N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:25]=[N:26][C:22]=2[CH:21]=1>CN(C=O)C>[NH2:12][C:10]1[N:11]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:7]2[N:15]=[N:14][N:13]([CH2:19][C:20]3[CH:35]=[CH:34][C:23]4[N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[N:25]=[N:26][C:22]=4[CH:21]=3)[C:8]=2[N:9]=1
Reactant: CC(C)(C)OC(=O)n1nnc2cc(CBr)ccc21
Reactant: Nc1nc(-c2ccco2)c2[nH]nnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nnc2cc(Cn3nnc4c(-c5ccco5)nc(N)nc43)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (404 mg, 2 mmol) in DMF (4 mL) was treated with NaH (60% dispersion, 80 mg, 2 mmol), stirred at room temperature for 10 min, treated with a solution of tert-butyl 5-(bromomethyl)-1H-benzotriazole-1-carboxylate (as a mixture with the 6-bromomethyl regioisomer) (624 mg, 2 mmol) in DMF (2 mL) and stirred overnight. The mixture was concentrated in vacuo and purified by chromatography [SiO2, isohexane:EtOAc (2:1)] to give tert-butyl 5-(5-amino-7-(2-furyl)-3H-triazolo[4,5-d]pyrimidin-3-yl)methyl-1H-benzotriazol-1-carboxylate (135 mg, 24%) (as a mixture with the 6-substituted regioisomer) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([CH3:12])[C:7](=[O:13])[C:6]=2[CH:14]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:31]=1)[C:20]([NH:22][C:23]1[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[F:1][C:2]1[C:3]([O:16][C:17]2[CH:18]=[C:19]([CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:31]=2)[C:20]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=2)=[O:21])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([CH3:12])[C:7](=[O:13])[C:6]=2[CH:14]=1
Reactant: CN1CCOc2cc(F)c(F)cc2C1=O
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2cc3c(cc2F)C(=O)N(C)CCO3)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Yield: 6.6 %

Procedure:
A mixture of 7,8-difluoro-4-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (725 mg, 2.0 mmol), 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (600 mg, 1.97 mmol) and potassium carbonate (550 mg, 3.88 mmol) in DMA (10 mL) was heated to 160° C. for 5 hours. Water (20 mL) was added to the reaction and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with water (2×30 mL) and brine (2×30 mL), dried (MgSO4), filtered and evaporated to give a yellow oil. This was purified by column chromatography on silica, eluting with 20-100% ethyl acetate in isohexane, to give the desired compound as a foam (65 mg).