Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3]Br.[OH:5][N:6]([CH:22]([CH3:24])[CH3:23])[C:7]([NH:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH:22]([N:6]1[C:7](=[O:8])[N:9]([C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:19])([F:20])[F:21])=[O:11])[CH2:3][CH2:2][O:5]1)([CH3:24])[CH3:23]
Reactant: BrCCBr
Reactant: CC(C)N(O)C(=O)NC(=O)c1cnccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)N1OCCN(C(=O)c2cnccc2C(F)(F)F)C1=O
Reaction time: 3 h

Procedure:
1,2-Dibromoethane (0.06 ml) was added to a suspension of 1-hydroxyl-1-isopropyl-3-(4-trifluoromethyl-3-pyridylcarbonyl)urea (0.20 g) and potassium carbonate (0.20 g) in N,N-dimethylformamide at 20° C., and stirred for 3 hours. Ethyl acetate and water were added and the organic phase dried (magnesium sulfate), evaporated and the residue purified by column chromatography on silica gel, eluting with n-hexane/ethyl acetate (2:1), to give 2-isopropyl-4-(4-trifluoromethyl-3-pyridylcarbonyl)-perhydro-1,2,4-oxadiazin-3-one (0.25 g, Compound U-3).
Reaction SMILES: Br[C:2]1[C:3]([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][CH2:27][CH3:28])=[N:4][C:5]([N:10]([CH3:12])[CH3:11])=[N:6][C:7]=1[O:8][CH3:9].C(N)CN.[Li]CCCC.C[O:39]B(OC)OC.OO.Cl>C1COCC1.O>[CH3:11][N:10]([CH3:12])[C:5]1[N:4]=[C:3]([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][CH2:27][CH3:28])[C:2]([OH:39])=[C:7]([O:8][CH3:9])[N:6]=1
Reactant: COB(OC)OC
Reactant: CCCCCCCCCCCCCCCCc1nc(N(C)C)nc(OC)c1Br
Agent: Cl
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: NCCN
Product: CCCCCCCCCCCCCCCCc1nc(N(C)C)nc(OC)c1O
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution at −5° C. containing 500 mg (1.10 mmol) of 5-bromo-4-hexadecyl-6-methoxy-N,N-dimethylpyrimidin-2-amine in 10 mL of anhydrous THF were added 166 μL (1.10 mmol) of N,N,N,N-tretamethyl ethylenediamine followed by 1.72 mL (2.75 mmol) of 1.6 M solution of n-BuLi in hexanes. The reaction mixture was stirred at −5° C. for 20 min. Then to the mixture were added 369 μL (3.30 mmol) of trimethoxy boron and the reaction mixture was stirred at 23° C. for 1 h. Then to reaction mixture were added 2.84 mL of 30% aq. H2O2 The reaction mixture was then stirred for 30 min and poured into 100 mL of water. The mixture was neutralized with diluted aq. HCl and extracted with two 100-mL portions of ethyl acetate. The combined organic solution was washed with a 100-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (10×3 cm). Elution with 4:1 hexanes-ethyl acetate afforded the expected product as white solid: yield 240 mg (55%); mp: 78-79° C.; silica gel TLC Rf=0.50 (4:1 hexanes-ethyl acetate); 1H-NMR (dmso-d6) δ 0.81 (t, 3H, J=6.0 Hz), 1.23-1.19 (br m, 26H), 1.52 (quint, 2H, J=6.8 Hz), 2.46 (dd, 2H, J=7.2, 7.2 Hz), 2.97 (s, 6H) and 3.82 (s, 3H); 13C NMR (dmso-d6) δ 14.38, 22.53, 27.65, 29.14, 29.27, 29.32, 29.38, 29.43, 29.46, 29.46, 29.46, 29.46, 29.46, 29.46, 31.20, 31.73, 37.27, 37.27, 53.13, 127.10, 155.54, 156.81 and 159.70.
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[C:31]1([C:37]2([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O.C(=O)([O-])[O-].[K+].[K+].[CH3:52][O:53][C:54]1[CH:62]=[CH:61][C:60]([N:63]2[CH:67]=[N:66][N:65]=[N:64]2)=[CH:59][C:55]=1[C:56](Cl)=[O:57]>CC(C)=O>[CH3:52][O:53][C:54]1[CH:62]=[CH:61][C:60]([N:63]2[CH:67]=[N:66][N:65]=[N:64]2)=[CH:59][C:55]=1[C:56]([N:39]1[CH2:40][CH2:41][C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH2:42][CH2:43][OH:44])[CH2:38]1)=[O:57]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)Cl
Reactant: OCCC1(c2ccccc2)CCNC1
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCO)(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (3.49 g,6.48 mmol) and acetone (20 mL), water (6 mL), and potassium carbonate (2.70 g, 19.5 mmol). Cool to 0° C. in an ice bath. After 30 minutes, add dropwise a solution of 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (7.4 mmol) in acetone (20 mL). Warm to ambient temperature. After 18 hours, partition the reaction mixture between ethyl acetate and saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]([O:18][CH2:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:11]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH:25]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: Clc1cc(COCc2ccccc2)ncn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: c1ccc(COCc2cc(Oc3ccc4[nH]ccc4c3)ncn2)cc1

Procedure:
To a solution of 5-hydroxy indole (1.33 g, 10 mmol) and 4-benzyloxymethyl-6-chloro-pyrimidine (2.35 g, 10 mmol) in acetonitrile (20 mL) is added DBU. After 16 h at rt the solution is concentrated under reduced pressure. The residue is purified by FCC (EtOAc/Heptane from 0% to 40%) to give 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-1H-indole. MS (ESI) m/z 447.0 (M+1).
Reaction SMILES: Cl.Cl.[C:3]1([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:21][C:22]([C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)=[O:23].CC(C)([O-])C.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([C:24]1[CH:29]=[CH:28][C:27]([N:18]2[CH2:19][CH2:20][C@H:16]([NH:15][C@@H:13]([C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=[CH:5][CH:4]=3)[CH3:14])[CH2:17]2)=[CH:26][CH:25]=1)(=[O:23])[CH3:21]
Reactant: C[C@@H](N[C@H]1CCNC1)c1cccc2ccccc12
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(N2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In 2 ml of toluene were suspended 200 mg of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride, 127 mg of 4-bromoacetophenone, 214 mg of sodium tert-butoxide, and 76 mg of biphenyl-2-yl-di-tert-butylphosphane, and nitrogen gas was ventilated for 15 minutes. After adding 59 mg of tris(dibenzylideneacetone)dipalladium to the mixture, the reaction vessel was sealed and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was separated and concentrated, and the obtained residue was purified by silica gel column chromatography to obtain (S)-1-(4-acetylphenyl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine (2) In 2 ml of tetrahydrofuran was dissolved (S)-1-(4-acetylphenyl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine obtained in the above-mentioned (1), and 0.2 ml of a solution of 4M hydrochloric acid-dioxane was added to the mixture. The precipitated solids were collected by filtration, washed with ether and dried to obtain 90 mg of (S)-1-(4-acetylphenyl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine hydrochloride (the following Table A1, Example 1.082).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:11]1[CH:16]2[CH2:17][CH2:18][CH:12]1[CH2:13][CH:14]([N:19]([C:24]1[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=1)[N:29](C1CCCCO1)[N:28]=[CH:27]3)[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:15]2)[CH2:9][CH3:10].C(=O)([O-])O.[Na+]>ClCCl>[NH:29]1[C:30]2[C:26](=[CH:25][C:24]([N:19]([CH:14]3[CH2:15][CH:16]4[N:11]([CH2:8][CH2:9][CH3:10])[CH:12]([CH2:18][CH2:17]4)[CH2:13]3)[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:32][CH:31]=2)[CH:27]=[N:28]1
Reactant: CCCN1C2CCC1CC(N(c1ccc3c(cnn3C3CCCCO3)c1)S(C)(=O)=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN1C2CCC1CC(N(c1ccc3[nH]ncc3c1)S(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.9 %

Procedure:
Trifluoroacetic acid (0.2 ml) was added to a solution of N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-N-(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-methanesulfonamide (19 mg, 0.0425 mmol) in dichloromethane (0.8 ml), and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a preparative thin-layer chromatography (200×200×0.5 mm, eluent: chloroform/methanol=9/1) to obtain N-(1H-indazol-5-yl)-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)methanesulfonamide (6 mg, 40%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1C=CC=CC=1>C(N(CC)CC)C>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)c1ccccc1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and benzoyl chloride in substantially the same manner as described in Example 61 with one change: pyridine was used as a base instead of triethylamine; off-white solid: MS (EI) m/z 497.2 (M+H)+; 1H NMR (DMSO-d6): δ 7.03 (d, J=7.6 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 7.39 (t, J=8.0 Hz, 2H), 7.50-7.95 (m, 10H), 8.05 (d, J=7.7 Hz, 1H), 8.36 (d, J=7.0 Hz, 1H), 9.16 (s, 1H), 10.33 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.[Cl-].[Al+3].[Cl-].[Cl-].[I:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>[N+](C)([O-])=O.C(OCC)C>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[I:23])[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: O=C(Cl)c1ccccc1I
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3ccccc3I)ccc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
250 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1benzopyran were dissolved in 10 ml of nitromethane and cooled in an ice-bath under a nitrogen atmosphere. 280 mg of finely powdered aluminum chloride were added followed, after 5 minutes, by 700 mg of 2-iodobenzoyl chloride. After stirring at 0° C. for 30 minutes and at room temperature for 1 hour the mixture was diluted with diethyl ether and washed with sodium hydroxide solution. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:2) for the elution to give 230 mg of 3,4-dihydro-2,2-dimethyl-6-(2-iodobenzoyl)-4-(2-pyridyl)-2H-1-benzopyran.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[Br:13]Br>C(O)(=O)C>[Br:13][CH:6]1[C:5](=[O:12])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[O:8][CH2:7]1
Reactant: BrBr
Reactant: O=C1CCOc2ccc(F)cc21
Solvent: CC(=O)O
Product: O=C1c2cc(F)ccc2OCC1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 6-fluorochroman-4-one (21.0 g, 126 mmol) in acetic acid (105 ml) is added bromine (6.5 ml, 126 mmol) at such a rate as to not raise the temperature above 25° C. After the addition is complete, the reaction is allowed to stir for 2 hours before pouring into 1 liter of ice. The resulting mixture is stirred overnight. The precipitate which formed is filtered and placed in drying oven to produce 21 g of 3-bromo-6-fluorochroman-4-one.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:11][O:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCCCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: c1ccc(CCCC2CO2)cc1

Procedure:
5-Phenylpent-1-ene (14.2 g, 0.0973 mol) and m-chloroperbenzoic acid (16.79 g, 0.0973 mol) in dichloromethane (300 ml) was stirred at room temperature for 4 hours. The solution was washed with saturated aqueous sodium hydrogen carbonate solution and dried (MgSO4). The solvent was evaporated off under reduced pressure to give an oil which was distilled to give 2-(3-phenylpropyl)oxirane (b.p. 85° C., 0.4 mm.Hg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)(=[O:11])=[O:10].[CH3:25][O-:26].[Na+].[ClH:28]>CO.O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([O:26][CH3:25])[CH:5]=[CH:4][C:3]=1[S:9]([CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)(=[O:10])=[O:11].[ClH:28]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(F)cc2F)CC1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2CCNCC2)c(F)c1
Temperature: 45 °C
Reaction time: 0.33 h

Procedure:
To a suspension of tert-butyl 4-((2,4-difluorophenyl)sulfonyl)piperidine-1-carboxylate (50 mg, 0.138 mmol) in MeOH (461 μL) was added sodium methoxide (25.6 μL, 0.138 mmol, 5.4 M in MeOH) dropwise. The reaction mixture was allowed to stir at 45° C. for 20 min then concentrated in vacuo. Boc deprotection was carried out by addition of HCl (138 μL, 0.553 mmol, 4 M in dioxane) to the crude reaction mixture in 300 μL dioxane. Stirring at 50° C. for 24 h followed by concentration in vacuo yielded the title compound as its HCl salt (57 mg) as a white solid (10:1 regioisomeric mixture). ESI-MS m/z [M+H]+274.00.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[N:52]1([CH2:61][C:62](O)=[O:63])[CH:60]=[C:58]([CH3:59])[C:56](=[O:57])[NH:55][C:53]1=[O:54]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:16][N:17]=1)(=[O:12])=[O:11])[C:62](=[O:63])[CH2:61][N:52]1[CH:60]=[C:58]([CH3:59])[C:56](=[O:57])[NH:55][C:53]1=[O:54])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2)s1
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2)s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To the solution of N-{2-[5-(4-Chlorophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester (4.05 g, 10 mmol) in 30 mL of DMF, were added 1.68 g (11 mmol) of 1-hydroxybenzotriazole monohydrate, 2.27 g (11 mmol) of dicyclohexylcarbodiimide and 1.84 g (10 mmol) of (thymin-1-yl)-acetic acid. The reaction mixture was stirred for 3 hours at room temperature. The precipitated dicyclohexylurea was filtered off and the filtrate was concentrated in vacuo, followed by column chromatography on silica gel to give the title compound (4.85 g, 8.5 mmol, 85%). 1H NMR (500 MHz; DMSO-d6) δ 11.28 (s, 0.6H), 11.26 (s, 0.4H), 9.15 (brs, 0.6H), 9.00 (brs, 0.4H), 8.07 (d, 2H), 7.67 (d, 2H), 7.31 (s, 0.6H), 7.24 (s, 0.4H), 4.65 (s, 1.2H), 4.47 (s, 0.8H), 4.31 (s, 0.8H), 4.16 (q, 0.8H), 4.06 (q, 1.2H), 4.03 (s, 1.2H), 3.55 (t, 1.2H), 3.45–3.38 (m, 2H), 3.23 (t, 0.8H), 1.73 (s, 3H), 1.21 (t, 1.2H), 1.16 (t, 1.8H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][C:22](=[O:23])[O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Reactant: O=C(Cl)Oc1ccccc1
Product: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)Oc1ccccc1

Procedure:
This compound was prepared according to the procedure of Example 35, Step 2, using 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and phenyl chloroformate as the starting materials. LCMS for C17H10BrFN5O5 (M+H)+: m/z=461.9, 463.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([C:15]([OH:17])=O)=[CH:8]2.[NH:18]1[CH2:27][CH2:26][CH2:25][C@H:19]1[C:20]([O:22][CH2:23][CH3:24])=[O:21].CCOC(OC(OCC)=O)=O.C(N(CC)CC)C>C(OCC)(=O)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([C:15]([N:18]1[CH2:27][CH2:26][CH2:25][C@H:19]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])=[CH:8]2
Reactant: COc1ccc(OC)c2c1C=C(C(=O)O)CC2
Reactant: CCOC(=O)[C@@H]1CCCN1
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CCCN1C(=O)C1=Cc2c(OC)ccc(OC)c2CC1
Reaction time: 0.08 h

Procedure:
To a DMF solution (40 ml) containing 9b (6.24 g, 26.2 mmole) and (S) (-)-ethyl prolinate (4.20 g, 29.3 mmole), a DMF solution (40 ml) of DEPC (4.70 g, 28.8 mmole) is added, and then a DMF solution (40 ml) of triethylamine (2.65 g, 26.2 mmole) is dropwise added thereto at 0° C. in 5 minutes. The resultant mixture is stirred at 0° C. for 2 hours and then at room temperature for 48 hours in a nitrogen stream. After completion of the reaction, the reaction mixture is diluted with ethyl acetate (1.2 liters), and the ethyl acetate solution is washed with 5% hydrochloric acid (120 ml×2), water (120 ml×2), a saturated aqueous solution of sodium chloride (120 ml×2), a saturated aqueous solution of sodium hydrogen carbonate (120 ml×2), water (120 ml×2) and a saturated aqueous solution of sodium chloride (120 ml×2) in order, dried over anhydrous magnesium sulfate and subjected to filtration and evaporation to afford the crude product 10b as a pale brown caramel (10.3 g, 104%), which is purified by column chromatography (silica gel, 250 g; solvent, ether) to obtain a pure product 10b as a colorless caramel (8.3 g, 83%). [α]D20 -10.3° (c=2.28, ethanol). IRνmaxfilm cm-1 : 1730 (CO2Et), 1635 (C=C), 1603 (CON). NMR (in CDCl3 ): 1.27 (3H, t, J=7.5Hz, CO2CH2CH3), 1.70-3.10 (8H, m, CH2CH2C= and NCH2CH2CH2), 3.50-3.92 (2H, m, N--CH2), 3.78 (6H, s, two OCH3), 4.17 (2H, q, J=7.5Hz, CO2CH2CH3), 4.50 (1H, m, NCHCO), 6.15 (1H, d, J=10.7Hz, one of aromatic protons), 6.29 (1H, d, J=10.7Hz, one of aromatic protons), 7.21 (1H, broad s, CH=).
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[N:6][C:7]([O:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:8][C:9]=2[CH3:11])[N:4]([CH3:26])[N:3]=1.[F-].[Cs+].[B-](F)(F)(F)F.CC([PH+](C(C)(C)C)C(C)(C)C)(C)C.[F:47][C:48]1[C:49]([Sn](CCCC)(CCCC)CCCC)=[N:50][CH:51]=[CH:52][CH:53]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl>[F:47][C:48]1[C:49]([C:2]2[C:10]3[C:5](=[N:6][C:7]([O:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH3:18])=[O:15])=[CH:8][C:9]=3[CH3:11])[N:4]([CH3:26])[N:3]=2)=[N:50][CH:51]=[CH:52][CH:53]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1F
Reactant: Cc1ccc([C@H](C)NC(=O)COc2cc(C)c3c(Cl)nn(C)c3n2)cc1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc([C@H](C)NC(=O)COc2cc(C)c3c(-c4ncccc4F)nn(C)c3n2)cc1
Temperature: 100 °C
Yield: 6.6 %

Procedure:
To a sealed tube were added (S)-2-((3-chloro-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)oxy)-N-(1-(p-tolyl)ethyl)acetamide (50 mg, 0.13 mmol), Pd[P(tBu)3)]2 (3.4 mg, 6.7 μmol), CsF (45 mg, 0.30 mmol), [(t-Bu)3PH]BF4 (3.9 mg, 0.013 mmol) and Pd2(dba)3 (6.1 mg, 6.7 μmol). The tube was evacuated and flushed 3 times with argon and then 3-fluoro-2-tributylstannyl-pyridine (104 mg, 0.27 mmol) in dioxane (1 ml) was added and the suspension heated at 100° C. for 16 h. After cooling to rt, CH2Cl2 and NaHCO3 solution were added and the phases separated. The organic layers were washed with water, dried over Na2SO4 and the solvents removed under reduced pressure. Purification using preparative reverse phase chromatography (LC SunFire C18 OBD column) followed by liberation of the free base (SPE cartridge SCX-1, eluent 7M NH3 in methanol) yielded the title compound (3.7 mg, 6%). [1H-NMR (DMSO-d6, 600 MHz) δ 8.59 (d, 1H), 8.54 (d, 1H), 7.91 (t, 1H), 7.62-7.58 (m, 1H), 7.18 (d, 2H), 7.08 (d, 2H), 6.64 (s, 1H), 4.96 (q, 1H), 4.87 (d, 1H), 4.84 (d, 1H), 3.89 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H), 1.37 (d, 3H); HPLC-MS RtJ=1.08 min; [M+H]+=434.1]
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:6]=[C:5]([NH:16][CH2:17][CH2:18][OH:19])[N:4]=1.[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:32][CH2:33][CH3:34])[C:30]=1[F:31])[CH:26]=O)[CH3:21].C(N(C(C)C)C(C)C)C.C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:32][CH2:33][CH3:34])[C:30]=1[F:31])[CH2:26][N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:7]2[N:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([NH:16][CH2:17][CH2:18][OH:19])[N:6]=2)[CH2:15][CH2:14]1)[CH3:21]
Reactant: COc1nc(NCCO)nc(NC2CCNCC2)n1
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(Nc3nc(NCCO)nc(OC)n3)CC2)cc(OCC)c1F
Temperature: 50 °C
Yield: 45.5 %

Procedure:
To a solution of 2-[4-methoxy-6-(piperidin-4-ylamino)-[1,3,5]triazin-2-ylamino]-ethanol (0.19 g, 0.71 mmol, 1.0 equiv; intermediate C26) and 3,5-diethoxy-4-fluoro-benzaldehyde (0.17 g, 0.78 mmol, 1.1 equiv; intermediate D12) in ethanol (10 mL) under an atmosphere of Ar was added N-ethyl diisopropylamine (0.28 mL, 0.21 g, 1.63 mmol, 2.29 equiv) and glacial acetic acid (0.10 mL, 0.10 g, 1.67 mmol, 2.35 equiv) and the mixture heated to 50° C. for 2 h. After cooling down to 30° C., sodium cyanoborohydride (0.12 g, 1.91 mmol, 2.7 equiv) was added and the reaction mixture heated again to 50° C. for 1.5 h. It was then poured into crashed ice, the pH of the water phase adjusted to ˜10 by addition of a sat. solution of sodium carbonate and the mixture extracted three times with dichloromethane. The combined organic phases were washed with water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 0.15 g (45%) of the title compound as light yellow oil. MS (ISP): 465.2 [M+H]+.