Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[C:9]([N:18]([CH3:20])[CH3:19])([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:10])=[CH:4][CH:3]=1.[NH2:22][CH2:23][CH2:24][CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[C:9]([N:18]([CH3:20])[CH3:19])([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(F)cc1
Reactant: NCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(NCCCO)cc1
Reaction time: 12 h

Procedure:
10.0 g (0.035 mol) of 1-(4-fluorophenyl)-2-dimethylamino-2-benzyl-propan-1-one and 18.4 g (0.25 mol) of 3-amino-1-propanol are dissolved in 20 ml of dry dimethylacetamide, and the solution is heated up to 150° C. together with 9.7 g (0.07 mol) of potassium carbonate, and stirred overnight (about 12 hours). After the solution is cooled down, it is poured into 300 ml of water and extracted with toluene. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After distilling off the toluene, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:1) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm]:1.14 (s, 3H), 1.50 (br, 1H), 1.93 (m, 2H), 2.33 (s, 6H), 2.96 (d, 1H), 3.37 (m, 2H), 3.42 (d, 1H), 3.85 (m, 2H), 4.45 (br, 1H), 6.56 (d, 2H), 6.89-6.91 (m, 2H), 7.10-7.12 (m, 3H), 8.45 (d, 2H).
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][C@H:4]1[CH2:5][OH:6].[C:10]1([CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[C:10]1([CH2:16][CH2:17][CH2:18][C:19]([N:3]2[CH2:9][CH2:8][CH2:7][C@H:4]2[CH2:5][OH:6])=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: OC[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCCc1ccccc1)N1CCC[C@H]1CO
Temperature: 0 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Aqueous sodium hydroxide (1N, 25 ml) is added to a solution of 2.0 g of L-prolinol (U.S. Pat. No. 3,935,280) in 50 ml of CH2Cl2. After cooling the reaction mixture to 0° C., 4.0 g of 4-phenylbutyric acid chloride is added and the reaction is stirred vigorously for 4 hours at 0° C., followed by 1 hour at room temperature. The reaction is diluted with an equal volume of CH2Cl2 and the layers separated. The organic phase is washed with 30 ml of water and dried over Na2SO4 /K2CO3. The solvent is evaporated to yield 4.4 g of N-(4-phenylbutanoyl)-L-prolinol having IR peaks at 3280 and 1605 cm-1, [α]D25 =-40.3° (methanol). 20.5 g of N-methyl-N,N'-dicyclohexylcarbodiimidium iodide (Angew. Chem., Int. Ed. 11, 229 (1972) is added to a solution of 5.3 of R-(-)-3-benzyloxy-2-methylpropanol (Helv. Chim. Acta 60, 925 (1977) in 200 ml dry tetrahydrofuran under nitrogen and the reaction is stirred at room temperature for 14 hours. The solvent is evaporated and 20 ml of ether and 5 ml of pentane are added. The resulting yellow solid is collected and the mother liquors are chromatographed on 200 g of silica gel with pentane to yield 6.68 g of the S(+)-3-benzyloxy-2-methylpropyl iodide having Rf=0.60 (9:1 of pentane: ether/Si°2), [ α]D25 =+11.1° (MeOH). N-(4-phenylbutanoyl)L-prolinol is dissolved in 2 ml of dry tetrahydrofuran and added dropwise to a solution of lithium diisopropylamide (15.6 m moles) in 50 ml of tetrahydrofuran at 0° C. under nitrogen. After 30 minutes at 0° C., 2.03 g of S-(+)-3-benzyloxy-2-methylpropyl iodide is added dropwise in 2 ml of dry tetrahydrofuran. The reaction is stirred at 0° C. for 5 hours, at -15° C. for 15 hours and quenched at 0° C. with excess saturated ammonium chloride solution. The reaction mixture is diluted with 30 ml of ether. The layers are separated and the organic phase is washed with 16 ml of 1N HCl, 15 ml of brine, 15 ml of saturated sodium bicarbonate and dried over sodium sulfate. Evaporation of solvent yields 3.6 g of an oil which is filtered through 60 g of silica gel with ethyl acetate to yield 2.3 g of N-(R,R-5-benzyloxy-4-methyl-2-phenethylpentanoyl) L-prolinol having Rf 0.51 (EtoAc/SiO2).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].FC(F)(F)C(O)=O>CS(C)=O>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:17][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1ccccc1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
1.62 g (10 mmole) of N,N′-carbonyldiimidazole were added to a dimethyl sulfoxide (10 ml) solution including 1.12 g (10 mmole) of benzoic acid, followed by stirring at room temperature for 1 hour. After the addition of 2.16 g (20 mmole, 2 equivalents) of 1,2-phenylenediamine, 1.9 ml of trifluoroacetic acid were added dropwise at room temperature. After reaction had been further carried out at room temperature for 15 hours, a post-treatment was performed in the same manner as in Example 6 to obtain 1.27 g (yield: 59%) of N-(2-aminophenyl)benzamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:27])[F:28])=[N:20][C:21]([C:22]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCOCC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 88.8 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (60 mg, 0.109 mmol), morpholine (19 mg, 0.218 mmol) and bis(2-oxo-3-oxazolidinyl) phosphonic chloride (53.5 mg, 0.218 mmol) were dissolved in 5 mL of dichloromethane under stirring, and triethylamine (0.1 mL, 0.65 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight until thin lay chromatography showed the starting material disappeared, and was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(morpholine-4-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 3a (60 mg, yield 89%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[C:9](O)[CH:8]=[CH:7][C:6]=1[NH:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20].C(=O)([O-])[O-].[K+].[K+].[O:28]([C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38]Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[C:9]([CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:36]=2)[CH:8]=[CH:7][C:6]=1[NH:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20]
Reactant: COC(=O)Cc1cc(O)ccc1Nc1c(Cl)cccc1Cl
Reactant: ClCc1cccc(Oc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: COC(=O)Cc1cc(Cc2cccc(Oc3ccccc3)c2)ccc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A mixture of 2-[(2,6-dichlorophenyl)amino]-5-hydroxy benzene acetic acid methyl ester (2.5 g, 7.67 mmol) of Example 2F, powdered anhydrous potassium carbonate (0.55 g, 4 mmol), tetrabutylammonium iodide (0.050 g) and dry acetonitrile (50 mL) is stirred at room temperature under nitrogen for 30 min. To the slurry is then added 3-phenoxybenzylchloride (2 g, 9.17 mmol) and the mixture is placed in an oil bath maintained at 65°-70° C. overnight. The solvent is removed and the residue partitioned between water and ethyl acetate (50 mL each). The organic phase is washed with brine and dried (Na2SO4). The solvent is evaporated and the residue (brown oil, 4.2 g) is purified by flash chromatography (on silica Merck 60, hexane-ethyl acetate 85:15) to give the title product (yellow oil, 2.83 g, 73%).
Reaction SMILES: C(N[C:9](=[O:36])[CH:10]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[N:11]1[C:15]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C@H:21]([O:28][CH3:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C1C=CC=CC=1.N([O-])=[O:38].[Na+].[Li+].[OH-].OO>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH:30]1([CH:10]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@H:21]([O:28][CH3:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]([OH:38])=[O:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CO[C@H](c1ccccc1)c1nc2cc(F)ccc2n1C(C(=O)NCc1ccccc1)C1CCCCC1
Reactant: O=N[O-]
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CO[C@H](c1ccccc1)c1nc2cc(F)ccc2n1C(C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-benzyl-2-cyclohexyl-2-[5-fluoro-2-((R)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetamide (5.91 g, 12.17 mmol, 1.0 equiv) in a mixture of acetic acid (40 mL) and acetic acid anhydride (80 mL) was added at 0° C. in several small portions sodium nitrite (18.47 g, 267.76 mmol, 22.0 equiv) within 1 h. The reaction mixture was stirred overnight allowing to warm up to rt. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with diethyl ether. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was taken up in a mixture of THF:water (3:1, 40 mL) and a pre-prepared solution of LiOH (2.91 g, 121.71 mmol, 10.0 equiv) in hydrogen peroxide (2.76 g, 24.84 mL, 243.42 mmol, 20.0 equiv; 30% solution in water) was added and stirred at rt for 30 min. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 4 by addition of acetic acid and the aqueous layer extracted with diethyl ether. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. Purification by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% acetic acid)/ethyl acetate yielded the title compound as two clean diastereoisomers in 1.52 g (32%, isomer A) and 1.50 g (31%, isomer B) together with a mixed fraction of 0.90 g (19%). Isomer A: MS (ISP): 397.3 [M+H]+. Isomer B: MS (ISP): 397.1 [M+H]+. Mixed fraction: MS (ISP): 397.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][O:4][CH2:3]1.[S:29](N)([NH2:32])(=[O:31])=[O:30]>O1CCOCC1.C(OCC)(=O)C>[CH3:17][C:15]1[CH:16]=[C:11]([C:8]2[S:7][C:6]([C:2]3([NH:1][S:29](=[O:31])(=[O:30])[NH2:32])[CH2:3][O:4][CH2:5]3)=[N:10][CH:9]=2)[CH:12]=[C:13]([NH:18][C:19]2[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=2)[CH:14]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(N)COC3)s2)c1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(N)(=O)=O)COC3)s2)c1
Temperature: 100 °C
Yield: 55.7 %

Procedure:
To a solution of N-{3-[2-(3-aminooxetan-3-yl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (Example 59, 25 mg, 0.061 mmol) in dioxane (600 uL), sulfamide (70 mg, 0.725 mmol) was added. The reaction mixture was stirred at 100° C. The resulting mixture was stirred at 100° C. for 4 days. The mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (10-100% ethyl acetate in hexanes) and lyophilized to afford N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}sulfuric diamide (16.3 mg, 0.034 mmol, 54.6% yield) as a pale yellow solid. MS ESI: [M H]+ m/z 487.0. 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 2H), 8.85 (m, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 7.51 (s, 1H), 7.28 (m, 1H), 7.17 (s, 1H), 6.98 (s, 2H), 5.02 (m, 2H), 4.84 (m, 2H), 2.32 (s, 3H). rhSYK activity=+++
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][C:24]([S:30](Cl)(=[O:32])=[O:31])=[CH:25][CH:26]=2)[N:21]=1.C(Cl)Cl>CO.C(Cl)Cl>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:24]2[CH:23]=[C:22]3[C:27]([CH:28]=[CH:29][C:20]([O:19][CH3:18])=[N:21]3)=[CH:26][CH:25]=2)(=[O:31])=[O:32])[C:4]1=[O:17])#[N:13]
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2n1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2n1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride (0.305, 1.2 mmol) as in EXAMPLE 24, Part B using 2-methoxyquinoline-7-sulfonyl chloride (0.30 g, 1.16 mmol) in place of 6-methoxynaphthalene-2-sulfonyl chloride. 2-Methoxy-quinoline-7-sulfonic acid {1-[3-cyanobenzyl]-2-oxopyrrolidin-3-(S)-yl}amide is obtained as a solid (0.27 g, 0.62 mmol) upon chromatography (CH2Cl2 to 3% MeOH/CH2Cl2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[C:11](=[O:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][CH2:29][CH2:30][Cl:31].CN(C=O)C>CC(C)=O>[Cl:31][CH2:30][CH2:29][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[C:11](=[O:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: CC(C)n1nc(-c2ccc(O)cc2)c2sccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(C)n1nc(-c2ccc(OCCCCl)cc2)c2sccc2c1=O
Yield: 98 %

Procedure:
A solution of the product of step 3 (858 mg, 3 mmol), K2CO3 (1.24 g, 3.0 eq.), and 3-bromo-1-chloropropane (0.3 mL, 1.05 eq.) in acetone:DMF (25 mL:3 mL) was heated to 80° C. overnight. The mixture was then filtered, washed with acetone, and concentrated to dryness to afford the product of step 4 (1.17 mg, 98% yield): Mp 92-4° C.; MS m/z 363 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]3[CH:14]=[C:15]([S:18]([N:21]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]2=3)=[C:4]([Br:36])[CH:3]=1.N(OC(C)(C)C)=O.[N:44]([Si](C)(C)C)=[N+:45]=[N-]>C(#N)C>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]3[CH:14]=[C:15]([S:18]([N:21]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]2=3)=[C:4]([Br:36])[CH:3]=1)=[N+:44]=[N-:45]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(N)cc2Br)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(N=[N+]=[N-])cc2Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(4-amino-2-bromophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.095 g, 0.162 mmol) in dry acetonitrile (1.617 mL) at 0° C. was added tert-butyl nitrite (0.027 mL, 0.226 mmol), followed by dropwise addition of azidotrimethylsilane (0.026 mL, 0.194 mmol). The resulting mixture was stirred for 20 minutes at RT. The reaction was concentrated under a vacuum, and purified via silica gel MPLC, eluting with a gradient of 0% to 100% ethyl acetate in heptanes to provide 4-(4-azido-2-bromophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as tan solid. The material was taken up in DCM (1.5 mL), and TFA (0.125 mL, 1.617 mmol) was added. The reaction was stirred at RT for 1.5 h, after which the reaction was concentrated under a vacuum. The material was purified by reverse-phase preparative HPLC using a Phenomenex Luna column, 5 micron, C18(2), 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 30% to 90% over 20 min to provide 4-(4-azido-2-bromophenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide 2,2,2-trifluoroacetate (0.0308 g, 0.051 mmol) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.55-3.63 (m, 1 H) 3.64-3.72 (m, 1 H) 4.27-4.34 (m, 1 H) 4.35-4.41 (m, 1 H) 6.10 (d, J=8.41 Hz, 1 H) 6.78 (d, J=4.69 Hz, 1H) 7.08-7.15 (m, 2 H) 7.22 (d, J=4.60 Hz, 1 H) 7.28 (dd, J=8.51, 2.54 Hz, 1 H) 7.53 (d, J=8.51 Hz, 1 H) 7.56 (d, J=2.54 Hz, 1 H) 12.55 (br. s., 1 H). m/z (ESI) 493.0 (M+H)+.
Reaction SMILES: [F:1][CH2:2][C:3]([NH2:17])([CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]#[N:5].C(N(CC)CC)C.[C:25](Cl)(=[O:35])[C:26]1[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:28](Cl)=[O:29].C1(=O)NC(=O)C2=CC=CC1=C2>ClCCl>[F:1][CH2:2][C:3]([N:17]1[C:28](=[O:29])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]2[C:25]1=[O:35])([CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]#[N:5]
Reactant: N#CC(N)(CF)CCCOCc1ccccc1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Agent: O=C1NC(=O)c2cccc1c2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC(CF)(CCCOCc1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a stirred mixture of 2-fluoromethyl-2-amino-5-benzyloxy-valeronitrile (74.8 g), triethylamine (100 g), and dry dichloromethane (450 ml), cooled in an ice bath, a solution of phthaloyldichloride (58 g) in dichloromethane (300 ml) is added slowly. Stirring is continued at room temperature overnight. The mixture is extracted with 2 N HCl (2×750 ml), washed with water (2×750 ml), dried carefully (Na2SO4), and evaporated to give a brown oil which, according to NMR analysis, contains some iso-phthalimide. The oil is dissolved in dry dichloromethane (500 ml), triethylamine (100 g) is added, and the mixture is refluxed for 3 hours. Work-up as described above gives an oil which is purified by flash-chromatography on silica (2 kg, petroleum ether/ethyl acetate 4:1). Crystallisation from ether gives the title compound (49.4 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]([C:11](OC)=[O:12])([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.[H-].C1(C)C=CC=CC=1>ClCCl>[CH:11]([C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:12]
Reactant: COC(=O)C1(C(=O)OC)CCOCC1
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)C1(C=O)CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of dimethyl tetrahydro-4H-pyran-4,4-dicarboxylate (3.9 g, 19.3 mmol) in dichloromethane (38 mL) was added dropwise a 1.01 M solution of diisobutylalminium hydride in toluene (38.2 mL, 38.6 mmol) at −78° C. over 30 min period. After being stirred at this temperature for 3 h, the mixture was quenched with followed by addition of aq. ammonium chloride and 2N hydrochloric acid. The mixture was allowed to warm to room temperature and filtered through a pad of celite. The filtrate was washed with water and dried over sodium sulfate and concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethylacetate 5:1) to affored 2.14 g (64%) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])=[CH:4][CH:3]=1>CO.[OH-].[Pd+2].[OH-]>[CH2:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[C:5]1[CH:4]=[CH:3][CH:2]=[CH:15][CH:14]=1
Reactant: Oc1ccccc1Cc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Oc1ccccc1Cc1ccccc1
Reaction time: 72 h
Yield: 66.8 %

Procedure:
To a solution of 2-(4-chlorobenzyl)phenol (618.5 mg, 2.83 mmol) in methanol (20 mL), a 20% palladium hydroxide catalyst (240 mg) was added. The mixture was stirred under a hydrogen atmosphere for three days, and then the catalyst was filtered off. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (348.4 mg, 67%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)=[CH:13][CH:12]=1
Reactant: CSc1nccc(Cl)n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSc1nccc(-c2ccc(Cl)cc2)n1
Temperature: 90 °C
Yield: 89.9 %

Procedure:
A mixture of 4-chloro-2-(methylthio)pyrimidine (3 g, 18.7 mmol), 4-chloro-phenylboronic acid (3.5 g, 22.3 mmol), tetrakis(triphenylphosphine)palladium (0) (0.43 g, 0.37 mmol), sodium carbonate (5.15 g, 48.5 mmol) in 1,2-dimethoxyethane (140 mL) and water (70 mL) was heated at 90° C. for 20 h under nitrogen. The cooled reaction mixture was concentrated In vacuo, diluted with water (50 mL), extracted with CH2Cl2 (2×100 ml), dried (Na2SO4) and the solvent removed in vacuo. Purification by Biotage™ chromatography (silica, 90 g) eluting with 10:1 to 2:1 cyclohexane:EtOAc afforded the title compound as a white solid (3.98 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:20][NH:21][C:22](=[O:71])[CH2:23][NH:24][C:25]([C@H:27]1[NH:45][C:44](=[O:46])[C@H:43]([CH2:47][CH2:48][CH2:49][NH:50]C(OC(C)(C)C)=O)[NH:42][C:41](=[O:58])[C@@H:40]([NH:59]C(OC(C)(C)C)=O)[CH2:39][C:38]2[CH:67]=[C:34]([CH:35]=[CH:36][C:37]=2[OH:68])[C:33]2=[CH:69][C:29](=[C:30]([OH:70])[CH:31]=[CH:32]2)[CH2:28]1)=[O:26])[CH2:9][CH2:10][CH2:11][NH:12]C(OC(C)(C)C)=O)(C)(C)C.[ClH:73]>O1CCOCC1>[ClH:73].[ClH:73].[ClH:73].[ClH:73].[NH2:59][C@H:40]1[CH2:39][C:38]2[CH:67]=[C:34]([CH:35]=[CH:36][C:37]=2[OH:68])[C:33]2=[CH:69][C:29](=[C:30]([OH:70])[CH:31]=[CH:32]2)[CH2:28][C@@H:27]([C:25]([NH:24][CH2:23][C:22]([NH:21][CH2:20][C@@H:8]([NH2:7])[CH2:9][CH2:10][CH2:11][NH2:12])=[O:71])=[O:26])[NH:45][C:44](=[O:46])[C@H:43]([CH2:47][CH2:48][CH2:49][NH2:50])[NH:42][C:41]1=[O:58]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)CNC(=O)[C@@H]1Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)N1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: NCCC[C@H](N)CNC(=O)CNC(=O)[C@@H]1Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H](N)C(=O)N[C@@H](CCCN)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.5 mg (0.011 mmol) of the compound from Example 178A are dissolved at 0° C. in 1 ml of dioxane. Then, 0.2 ml of a 4N hydrogen chloride solution in dioxane are added and the mixture is stirred at RT for 2 h. The mixture is evaporated to dryness in vacuo, and the residue is dried to constant weight under high vacuum.