Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.I[CH2:43][C:44]([NH2:46])=[O:45]>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[CH:14][N:13]2[CH2:43][C:44]([NH2:46])=[O:45])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)CI
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc([N+](=O)[O-])c3)cn2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc([N+](=O)[O-])c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 111.5 %

Procedure:
A mixture of 5-(3-nitrophenoxy)pyridin-2-amine (2.70 g, 11.7 mmol), p-toluenesulfonyl chloride (2.67 g, 14.0 mmol) and pyridine (20 mL) was stirred at 80° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give 4-methyl-N-[5-(3-nitrophenoxy)pyridin-2-yl]benzenesulfonamide (4.15 g, 92%) as a white solid. A mixture of 4-methyl-N-[5-(3-nitrophenoxy)pyridin-2-yl]benzenesulfonamide (4.15 g, 10.7 mmol) thus-obtained, N,N-diisopropylethylamine (2.44 mL, 14.0 mmol) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hr, iodoacetamide (2.59 g, 14.0 mmol) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (5.28 g, 99%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH3:14])[C:9]([CH:12]=C)=[N:10][CH:11]=1)[C:2]#[C:3][CH3:4].CC(C)=[O:17].O>O=[Os](=O)(=O)=O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH3:14])[C:9]([CH:12]=[O:17])=[N:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: C=Cc1ncc(OCC#CC)cc1C
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CC#CCOc1cnc(C=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
OsO4 (2.5 wt. % sol. in tert-Butanol) (0.86 mL, 0.0027 mol) was added to a stirred solution of 5-(but-2-yn-1-yloxy)-3-methyl-2-vinylpyridine (5.1 g, 0.027 mol) in acetone/water (100:100 mL) at 0° C. The reaction mixture was allowed to stir for 30 min at ambient temperature. Then NaIO4 (23.2 g, 0.108 mol) was added and the reaction mixture was allowed to stir for additional 4 h at ambient temperature. The reaction mixture was diluted with ice cold water (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel, eluting with 5-10% EtOAc in petroleum ether to give 5-(but-2-yn-1-yloxy)-3-methylpicolinaldehyde as an off white solid (3.6 g, 69.9%). MS m/z=189.9 [M+H]+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:46])([F:45])[C:17]1[CH:18]=[C:19]([C@H:27]([O:29][C@@H:30]2[C@@H:35]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[C@H:34]([CH:43]=O)[CH2:33][CH2:32][O:31]2)[CH3:28])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.FC(F)(F)C(O)=O.[CH2:54]1[C:58]2([CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[C@@H:57]([O:64][C:65]([C@@:67]23[C:73]([CH3:75])([CH3:74])[C@@:70]([CH3:76])([CH2:71][CH2:72]2)[C:69](=[O:77])[O:68]3)=[O:66])[CH2:56][O:55]1.C(N(CC)CC)C>ClCCl>[F:46][C:16]([F:15])([F:45])[C:17]1[CH:18]=[C:19]([C@H:27]([O:29][C@@H:30]2[C@@H:35]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)[C@H:34]([CH2:43][N:61]3[CH2:62][CH2:63][C:58]4([CH2:54][O:55][CH2:56][C@@H:57]4[O:64][C:65]([C@@:67]45[C:73]([CH3:74])([CH3:75])[C@@:70]([CH3:76])([CH2:71][CH2:72]4)[C:69](=[O:77])[O:68]5)=[O:66])[CH2:59][CH2:60]3)[CH2:33][CH2:32][O:31]2)[CH3:28])[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=1
Reactant: C[C@@H](O[C@H]1OCC[C@@H](C=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)O[C@H]1COCC13CCNCC3)OC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: C[C@@H](O[C@H]1OCC[C@@H](CN2CCC3(CC2)COC[C@@H]3OC(=O)[C@@]23CC[C@@](C)(C(=O)O2)C3(C)C)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 44.2 %

Procedure:
Solid sodium triacetoxyborohydride (107 mg, 0.504 mmol) was added to a stirred mixture of 2-[1-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-carbaldehyde (Description 11; 121 mg, 0.36 mmol), (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (4R)-2-oxa-8-aza-spiro[4.5]dec-4-yl ester trifluoroacetate (Description 10; 130 mg), triethylamine (0.1 ml, 0.72 mmol) and dichloromethane (3 ml) at room temperature. The mixture was stirred for 45 minutes, quenched with saturated aqueous NaHCO3 and extracted into dichloromethane. The organic extract was dried (Na2SO4) and concentrated. The residue was purified by preparative TLC (dichloromethane:methanol) to give the title compound (100 mg). The HCl salt was prepared and recrystallised from ethyl acetate:methanol.
Reaction SMILES: O=S(Cl)[Cl:3].[CH:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH2:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1.[CH3:16][CH2:17]O>>[NH2:15][C@@H:11]([C:12]([O:14][CH2:16][CH3:17])=[O:13])[C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][CH:9]=1.[ClH:3]
Reactant: CCO
Reactant: O=S(Cl)Cl
Reactant: N[C@@H](C(=O)O)c1ccccc1
Product: CCOC(=O)[C@H](N)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 71 h

Procedure:
SOCl2 (4.3 ml) was added to an EtOH suspension (150 ml) of D-phenylglycine (8.00 g) at −50° C. The cooling of the reaction was stopped and then stirred for 71 hours at room temperature. After concentrating the reaction mixture under reduced pressure, Et2O was added to the crude crystals and then filtered to obtain the D-Phg-OEt hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].O>CN(C)C=O>[CH3:18][C:10]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)([CH3:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=[N+]([O-])c1cn[nH]c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)n1cc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 4-nitro-1H-pyrazole (3.0 g) in N,N-dimethylformamide (50 mL) was added tert-butyl 2-bromo-2-methylpropanoate (15 mL), and the mixture was stirred at 80° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer 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 (hexane/ethyl acetate) to give the title compound (7.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][C@@H:18]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([NH:21][CH3:22])=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([NH:17][C@@H:18]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, MS (EI): m/e=374.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30](O)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH3:34][N:35]([CH:37]=O)[CH3:36].S(Cl)(Cl)=O>O1CCCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:25][C:18]4[CH:19]=[CH:33][C:15]([CH2:37][N:35]([CH3:34])[CH:36]5[CH2:7][CH2:6][O:5][CH2:1][CH2:2]5)=[CH:16][CH:17]=4)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCN3CC(C)C)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCCN3CC(C)C)cc1
Reaction time: 1 h

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (200 mg) in tetrahydrofuran (10 ml) was added a drop of DMF. Then, after adding thionyl chloride (0.042 ml), the mixture was stirred under nitrogen atmosphere for 1 hour. After the solvent and excessive thionyl chloride were distilled off under reduced pressure, the mixture was dissolved in tetrahydrofuran (15 ml). The solution was added dropwise to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]anilin (127 mg) and triethylamine (1.6 ml) in tetrahydrofuran (10 ml) at 0° C. under nitrogen atmosphere. After stirring the mixture at room temperature under nitrogen atmosphere overnight, water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (methanol:ethyl acetate=1:8) to give 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-((methyl(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (257 mg) as a yellow amorphous material (Compound 42).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH:11][C:12](=[O:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:4]([CH3:19])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(O)(=O)C.[Zn]>[NH2:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([CH3:19])[C:5]=1[NH:11][C:12](=[O:18])[CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17]
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1NC(=O)CC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(N)c1NC(=O)CC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
Zinc dust (16 g) was added in portions over 2 hours to N-(4-bromo-2-methyl-6-nitro-phenyl)-3,3-dimethyl-butyramide (2.74 g) in tetrahydrofuran (50 mL) and acetic acid (12 mL) cooled to 0° C., and then stirred 30 minutes at 25° C. The reaction mixture was poured into a suspension of sodium carbonate (16 g) in tetrahydrofuran and filtered through silica (50 g), which was washed with ethyl acetate (100 mL). The organic phase was concentrated in vacuo to furnish 2.47 g (100% yield) of the title compound as a pale red solid. LC-MS (m/z) 300 (MH+); tR=2.54, (UV, ELSD) 96%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.04 (s, 9H), 2.05 (s, 3H), 2.21 (s, 2H), 4.94 (s, 2H), 6.59 (d, 1H), 6.74 (d, 1H), 8.85 (s, 1H).
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[C:29]([CH2:30][C:31]([NH2:33])=[O:32])=[CH:28][CH:27]=[CH:26][N:25]=4)[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH3:38][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[C:29]([CH2:30][C:31]([NH2:33])=[O:32])=[CH:28][CH:27]=[CH:26][N:25]=4)[C:19]([C:34]([F:37])([F:35])[F:36])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1
Reactant: NC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
Formaldehyde (37 wt % in H2O; 16.5 μL, 0.222 mmol) was added to a suspension of 2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetamide (32) (22 mg, 0.044 mmol) in anhydrous methanol (5 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (94.0 mg, 0.444 mmol) was then added in one portion and the reaction was stirred at room temperature for 2 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (25 mL) and sat. aq. NaHCO3 (25 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL), the combined organic layers were washed with water (25 mL), brine (25 mL) and dried over Na2SO4. The solvent was removed under reduced pressure to yield a white solid. The solid was suspended in DCM (5 mL) and cyclohexane (20 mL) and filtered to afford the title compound (33) (16 mg, 72%) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.06 (s, 1H), 8.64 (s, 1H), 8.36 (dd, J=4.8, 1.7 Hz, 1H), 7.59 (dd, J=7.7, 1.2 Hz, 3H), 7.53 (s, 1H), 7.20-7.13 (m, 3H), 7.00 (s, 1H), 3.53 (s, 2H), 3.24 (s, 4H), 2.91 (d, J=10.6 Hz, 2H), 2.47-2.39 (m, 1H), 2.24 (s, 3H), 2.12-1.99 (m, 2H), 1.78-1.59 (m, 4H). LCMS Method C: rt 1.51, 1.579 min; m/z 499 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=[O:15])[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].O.OC1C2N=NNC=2C=CC=1.[F:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:29]=1[C:30](O)=[O:31].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[F:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:29]=1[C:30]([NH:2][CH:3]([C:9](=[O:15])[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:31]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: CCOC(=O)C(N)C(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(=O)c1c(F)cccc1F)C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
To a stirred mixture of crude ethyl 2-amino-3-oxo-3-(thiophen-2-yl)propanoate hydrochloride (0.44 g), hydroxybenzotriazole monohydrate (0.417 g, 2.7 mmol) and 2,6-difluorobenzoic acid (0.431 g, 2.7 mmol) in DMF (5.5 mL) was added triethylamine (0.38 mL, 5.2 mmol) followed by 1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (0.575 g, 3.0 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was partitioned between water and DCM. The organic phase was separated, washed with water, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using 20% EtOAc in hexane as eluant to afford ethyl 2-(2,6-difluorobenzamido)-3-oxo-3-(thiophen-2-yl)propanoate (0.123 g, 0.35 mmol, 20%). 1H NMR (CDCl3) 1.27 (3H, t), 4.28 (2H, m), 6.21 (1H, d), 7.00 (2H, t), 7.26 (1H, dd), 7.44 (2H, m), 7.83 (1H, dd), 8.20 (1H, dd). LCMS (1) Rt: 2.10 min; m/z (ES+) 354.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[N:14]=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:20]=[C:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[S:22][CH:23]=3)=[O:17])[CH:12]=[CH:11][CH:10]=2)[CH2:3]1>CCCCCC.CCO>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[N:14]=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:20]=[C:21]([C:24]4[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=4)[S:22][CH:23]=3)=[O:17])[CH:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: CC1CCCN(Cc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)C1
Solvent: CCO
Solvent: CCCCCC
Product: C[C@@H]1CCCN(Cc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)C1

Procedure:
1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea (50 mg, 0.12 mmol, Example 78) was separated by chiral HPLC (Chiraltech Chiralcel OJ 50×4.6 mm i.d.) using hexane/EtOH/DEA (90:10:0.2) to give a white solid. MS m/z: 409.3 (M+H). Calc'd for C21H24N6OS-408.52.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C>[C:1]([NH:4][C:5]1[C:14]([N+:25]([O-:27])=[O:26])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOc1cc(NC(C)=O)ccc1C(=O)OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOc1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
A mixture of 118.6 parts of methyl 4-(acetylamino)-2-ethoxybenzoate, 200 parts of acetic acid and 156 parts of acetic acid anhydride was stirred and heated to 50° C. After cooling to 15° C. (ice-bath) there were added dropwise 47.1 parts of fuming nitric acid 100% using a bromine funnel: an exothermic reaction occured. The temperature was kept at about 20° C. by cooling in an ice-bath. Upon completion, the temperature was allowed to rise to 40° C. and stirring was continued at this temperature for one hour. If necessary the whole was cooled with ice-water to keep the temperature at about 40° C. When the exothermic reaction was ceased, the whole was allowed to cool for one hour and was further cooled to 0° C. The reaction mixture was poured onto icewater while stirring. Upon stirring for one hour, the precipitated product was filtered off and dissolved in 1950 parts of dichloromethane. The solution was washed twice with 500 parts of water, dried, filtered and evaporated. The residue was crystallized overnight at room temperature from 2-propanol. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 67.6 parts (47.9%) of methyl 4-(acetylamino)-2-ethoxy-5-nitrobenzoate; mp. 110° C. (intermediate 32).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[N:10]=[CH:11][N:12]([C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1ccc(Oc2c[nH]cn2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Brc1ccc(Oc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1

Procedure:
To a cold (0° C.) solution of 4-(4-bromophenyloxy) imidazole (1.2 g, 5.0 mmol) and triethylamine (0.76 mL, 5.5 mmol) in DMF (5 mL) under an atmosphere of argon, solid trityl chloride (1.46 g, 5.3 mmol) was added. The resultant mixture was stirred at room temp overnight. The product mixture was concentrated onto silica gel, loaded onto a column of silica gel, and eluted with a mixture of 9:1 chloroform and acetone. Collection and concentration of appropriate fractions provided the titled compound as white powder.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>C1CCN2C(=NCCC2)CC1.C1CCCCC1>[CH3:17][O:16][C:12](=[O:15])[CH2:13][CH2:14][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:2](=[O:1])[CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: C=CC(=O)OC
Reactant: CCCC(=O)CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCCCC1
Product: CCCC(=O)C(CCC(=O)OC)(CCC(=O)OC)C(=O)OCC
Temperature: 60 °C
Reaction time: 2 h
Yield: 115.4 %

Procedure:
41.2 g (0.26 mol) of ethyl 3-oxo-hexanoate and 1.9 g (0.012 mol) of DBU were placed in a three necked round bottom flask, equipped with dropping funnel and reflux condenser. At room temperature, 56.3 g (0.65 mol) of methyl acrylate was slowly added drop by drop. After the exothermal behavior of the reaction leveled off, the reaction mixture was stirred at 60° C. for an additional two hours. The mixture was poured into cyclohexane and was washed with diluted hydrochloric acid and was subsequently washed with distilled water until the aqueous layer showed a neutral reaction. The organic layer was dried with sodium sulfate, the solvent was removed, and the residual addition product was isolated by fractional distillation in a vacuum. 50.0 g (0.15 mol) of 4-(ethoxycarbonyl)-4-(1-oxobutyl)-heptanedioic acid 1,7-dimethyl ester was obtained (yield: 58%; boiling point: 149° C. at 0.007 mbar; colorless).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:30]=[CH:29][C:28](=[O:31])[N:27]([CH3:32])[N:26]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][C:28](=[O:31])[N:27]([CH3:32])[N:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Cn1nc(O)ccc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)ccc1=O
Temperature: 160 °C
Yield: 39 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 3-hydroxy-1-methylpyridazin-6(1H)-one (Oakwood Products, Inc., West Columbia, S.C., USA; 24 mg, 0.19 mmol), and potassium carbonate (27 mg, 0.2 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Ethyl acetate and water were added, and the aqueous layer was extracted three times with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted twice with dichloromethane and the solvent was evaporated under high vacuum to give 4-[4-(1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (25 mg, 39%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 1.95-2.04 (m, 2H), 2.20-2.36 (m, 2H), 2.92-3.05 (m, 2H), 3.76 (s, 3H), 4.26-4.40 (m, 2H), 4.90-5.02 (m, 1H), 7.07 (d, 1H, J=9.7 Hz), 7.24 (d, 1H, J=9.7 Hz), 8.17 (s, 1H), 8.51 (s, 1H). Mass spectrum (ES) MH+=428. HRMS Calcd. for C20H26N7O4 (MH+): 428.2041. Found: 428.2040.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]([Cl:27])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:18]C)=[C:9]([S:11]([CH2:14][CH:15]2[CH2:17][CH2:16]2)(=[O:13])=[O:12])[CH:10]=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH:15]1([CH2:14][S:11]([C:9]2[CH:10]=[C:5]([O:4][C:3]3[C:2]([Cl:1])=[CH:23][C:22]([N+:24]([O-:26])=[O:25])=[CH:21][C:20]=3[Cl:27])[CH:6]=[CH:7][C:8]=2[OH:18])(=[O:12])=[O:13])[CH2:16][CH2:17]1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)CC1CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)CC3CC3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
To a solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-(cyclopropyl-methane-sulfonyl)-benzene (160 mg, 0.37 mmol) in CH2Cl2 (3 mL) was added boron tribromide (1M in CH2Cl2, 0.74 mL, 0.74 mmol). The resulting mixture was stirred at room temperature for 2 h and water (15 mL) was added. After stirring at room temperature for 1 h, the solution was extracted with EtOAc (3×20 mL). The combined organic extracts were dried and concentrated. The residue was purified by preparative TLC (100% CH2Cl2) to afford the title compound of Step D (76 mg). MS (APCl−) Calc.: 417.0, Found: 416.2 (M−1).