Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@@H:13]([CH:25]([CH3:27])[CH3:26])[C:14]([O:16][C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])=[O:15].[P:28](Cl)(Cl)(=[O:40])[O:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1.C(Cl)[Cl:44]>>[C:19]1([C@@H:17]([O:16][C:14](=[O:15])[C@@H:13]([N:12]=[P:28]([O:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][C:31]=2[Cl:44])=[O:40])[CH:25]([CH3:27])[CH3:26])[CH3:18])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: ClCCl
Reactant: CC(C)[C@H](N)C(=O)O[C@@H](C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(C)[C@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)C(=O)O[C@@H](C)c1ccccc1
Yield: 96 %

Procedure:
Using the general procedure for synthesizing naphthyl (aminoacid ester) phosphorochloridates, the tosylate salt of (S)-((S)-1-phenylethyl) 2-amino-3-methylbutanoate (2 g), naphthalen-1-yl phosphorodichloridate (1.33 g), TEA (1.41 mL) and DCM (60 mL) were combined to give (2S)-((S)-1-phenylethyl)-2-(chloro(naphthalen-1-yloxy)phosphorylamino)-3-methylbutanoate in an 96% yield (2.17 g) as a pale yellow thick oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([C:10](=O)[C:11]([O:13]CC)=O)[C:2]1=[O:17].[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(=O)C>[C:18]1([N:24]2[C:2](=[O:17])[C:3]3[C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=4[NH:1][C:11](=[O:13])[C:10]=3[NH:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(=O)C1C(=O)Nc2ccccc21
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2c2c(=O)n(-c3ccccc3)[nH]c12

Procedure:
Ethyl oxindole-3-glyoxylate (220 rag) in glacial acetic acid (2 ml) was heated under reflux for 10 minutes with phenylhydrazine (0.1 ml). The reaction was cooled and the resulting precipitate filtered and crystallised from methanol to give the title compound, mp>260° C.; 1H nmr (250 MHz, d6 -DMSO) δ5 11.86 (1H, broad s), 8.25 (1H, broad d), 7.86 (2H, d, J=8 Hz), 7.56 (2H, t, J=8 Hz) and 7.22-7.42 (4H, m).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH2:9]([N:16]1[CH2:21][CH:20]2[CH:18]([CH:19]2[CH:22]=O)[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCO>[CH2:9]([N:16]1[CH2:21][CH:20]2[CH:18]([CH:19]2[CH:22]=[N:2][OH:3])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=CC1C2CN(Cc3ccccc3)CC12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=CC1C2CN(Cc3ccccc3)CC12
Reaction time: 16 h
Yield: 91.2 %

Procedure:
Hydroxylamine hydrochloride (1.69 g, 22.84 mmol) and sodium acetate (2.45 g, 29.85 mmol) were added to a stirred solution of 3-benzyl-3-azabicyclo[3.1.0]hexane-6-carbaldehyde (1.60 g, 7.96 mmol) in EtOH (100 ml) at r.t. under N2. The reaction was allowed to stir for 16 h. The solvent was then removed in vacuo and the residue partitioned between DCM (100 ml) and aq. K2CO3 (100 ml). The organic layer was separated and the aqueous layer washed with DCM (100 ml). The combined organic layers were dried (MgSO4) and solvent removed in vacuo to give the title compound as a yellow oil (1.57 g, 91%-1:1 mixture of oxime isomers). LCMS purity 85%, m/z 217 [M+H]+, 1H NMR (300 MHz, d6-DMSO) δ: 1.65 (4H, m), 1.86 (1H, m), 2.29 (4H, d, J=9 Hz), 2.50 (1H, m), 2.91 (4H, dd, J=2.4, 9 Hz), 3.57 (4H, s), 6.05 (1H, d, J=9 Hz), 6.96 (1H, d, J=8.1 Hz), 7.21-7.34 (10H, m), 10.28 (1H, s), 10.59 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=2)[C:5]([O:16]C)=[C:4]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=2)[CH:3]=1.O.C(OCC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=2)[C:5]([OH:16])=[C:6]([C:8]2[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:7]=1
Reactant: COc1c(-c2cc(C)cc(C)c2)cc(C)cc1-c1cc(C)cc(C)c1
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2cc(C)cc(-c3cc(C)cc(C)c3)c2O)c1
Yield: 92 %

Procedure:
A mixed solution of 1 mL of water and 4 mL of dimethoxyethane was added into a flask into which 2,6-dibromo-4-methylanisole (400 mg, 1.43 mmol), 3,5-dimethylphenylboronic acid (658 mg, 4.39 mmol), palladium acetate (14 mg, 0.062 mmol), triphenylphosphine (60 mg, 0.23 mmol), and potassium phosphate (940 mg, 4.43 mmol) were already added, and then refluxed at normal temperature for 6 hours. After cooling to normal temperature, an ammonium chloride aqueous solution (5 mL) and 10 mL of diethylether were added thereto to separate an organic layer and extract residues using diethylether. The separated organic layer was dried with magnesium sulfate and volatile materials were removed to produce 453 mg of white 4-methyl-2,6-bis(3′,5′-dimethylphenyl)anisole solid (yield 96%). The anisole thus produced was dissolved in 5 mL of methylene chloride without separate purification, 3 mL of boron tribromide (1 M methylene chloride solution) were dropped thereonto at −78° C., and the reaction was carried out while the temperature was slowly increased to normal temperature. After the reaction, a mixed solution of water (5 mL) and diethylether (10 mL) was added to separate an organic layer and extract an aqueous solution layer using diethylether (5 mL×3), and the separated organic layer was dried. Residues from which volatile components were removed at reduced pressure were purified using a silica gel chromatography tube in a mixed solvent of hexane and methylene chloride to produce 0.41 g of white 4-methyl-2,6-bis(3′,5′-dimethylphenyl)phenol solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[S:7].Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:15]1[S:7][C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=2)=[N:8][C:21]=1[CH3:23])=[O:17])[CH3:20]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1cccc(C(F)(F)F)c1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2cccc(C(F)(F)F)c2)nc1C
Yield: 69.8 %

Procedure:
A solution of 3-trifluoromethyl-thiobenzamide (5 g, 23.2 mmol) and ethyl 2-chloro-acetoacetate (3.2 ml, 23.2 mmol) in ethanol (300 ml) was heated at reflux temperature for 14 hours. The solvent was removed under reduced pressure and the residue partitioned between ice water and ethyl acetate. The layers were separated and the aqueous phase extracted two times with ethyl acetate. The combined extracts were washed two times with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, cyclohexane/dichloromethane) to yield 5.1 g (16.2 mmol, 70%) of the title compound as colorless crystals.
Reaction SMILES: B(O[O-])=[O:2].[Na+].[CH3:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:40])[N:16]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[N:30]=[CH:29][C:28](B5OC(C)(C)C(C)(C)O5)=[CH:27][N:26]=4)[CH:20]=3)[N:17]=2)[CH:9]=[N:8]1>C1COCC1.O>[OH:2][C:28]1[CH:27]=[N:26][C:25]([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[CH2:18][N:16]2[C:15](=[O:40])[CH:14]=[CH:13][C:12]([C:10]3[CH:9]=[N:8][N:7]([CH3:6])[CH:11]=3)=[N:17]2)=[N:30][CH:29]=1
Reactant: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(B5OC(C)(C)C(C)(C)O5)cn4)c3)n2)cn1
Reactant: O=BO[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.50 g (85.1 mmol) of sodium perborate are added in portions with ice-cooling to a suspension of 13.4 g (28.4 mmol) of 6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one in 55 ml of THF and 55 ml of water, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is filtered off through kieselguhr with suction. The filtrate is evaporated to about half of the original volume in vacuo and adjusted to a pH of 1 using 2 N hydrochloric acid. The precipitate formed is filtered off with suction, washed with water and dried in vacuo: 2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one as pale-beige crystals; m.p. 239° C.; ESI 361.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([OH:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].I[CH2:17][CH3:18].Cl>CN(C)C=O.O>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([OH:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:18]
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(O)cc(OCC)c1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution of ethyl 3,5-dihydroxybenzoate (15.0 g) in N,N-dimethylformamide (180 ml) was gradually added sodium hydride (60% in oil, 3.30 g) at 0° C. and the mixture was stirred for 30 min. Iodoethane (12.9 g) was added and the mixture was further stirred for 2 hrs. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and ethyl 3-ethoxy-5-hydroxybenzoate (6.75 g, yield 39%) was obtained as crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). Recrystallization from diethyl ether-hexane gave colorless needle-shaped crystals. melting point: 62–63° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([N+:12]([O-])=O)[CH:3]=1.O.[Cl-].[NH4+]>C(O)C.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[C:4]([CH:3]=1)[NH2:12]
Reactant: O=[N+]([O-])c1cc(Br)ccc1C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Br)ccc1C(F)(F)F
Temperature: 80 °C
Yield: 89.5 %

Procedure:
To a suspension of 4-bromo-2-nitro-1-(trifluoromethyl)benzene (4.0 g, 14.9 mmol) in ethanol (230 mL), THF (85 mL), and water (40 mL) was added ammonium chloride (1.0 g, 18.8 mmol) and ferrous powder (5.06 g, 90 mmol). The resulting mixture was heated at 80° C. for 1 hr and the progress of the reaction was monitored by TLC. Upon complete consumption of staring material, the reaction mixture was filtered off while it was hot. The filtrate was evaporated under vacuum and the crude residue was diluted with ethyl acetate (100 mL) and washed with water (3×50 mL). The combined organic layer was washed with brine, dried over Na2SO4 and evaporated under vacuum to afford 5-bromo-2-(trifluoromethyl)aniline as a solid (3.2 g, 90%).
Reaction SMILES: CI.[O:3]=[C:4]1[NH:13][CH:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[S:22][CH3:23])[C:11]2[C:10](=[O:24])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.[C:35](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:35][N:13]1[CH:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[S:22][CH3:23])[C:11]2[C:10](=[O:24])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[C:4]1=[O:3]
Reactant: CSc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyliodide (70 μL, 1.10 mmol) is added to a mixture of 4-[2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-3-methylsulfanyl-benzonitrile (INTERMEDIATE 6; 177 mg; 0.354 mmol) and cesium carbonate (300 mg, 0.921 mmol) in DMF (2.4 mL) and the mixture is stirred at room temperature for 2 h. During the reaction, more cesium carbonate is added in small portions (total of 700 mg; 2.15 mmol). The reaction mixture is filtered and the filtrate is purified by reversed phase HPLC (Sunfire, gradient of acetonitrile in water, 0.1% TFA). Yield: 26 mg. ESI mass spectrum: [M+H]+=472; Retention time HPLC: 1.10 min (Z018_S04).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.N1C2C(=CC=CC=2)C=C(B(O)O)C=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2C.Br[C:46]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:47]=1[C:48]1([C:80]3[C:71](=[CH:72][C:73]4[O:78][CH2:77][CH2:76][O:75][C:74]=4[CH:79]=3)[O:70][CH2:69]1)[C:49](=[O:68])[N:50]2[CH:55](C1C=CC=CC=1)C1C=CC=CC=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:46]2[CH:54]=[CH:53][CH:52]=[C:51]3[C:47]=2[C:48]2([C:80]4[C:71](=[CH:72][C:73]5[O:78][CH2:77][CH2:76][O:75][C:74]=5[CH:79]=4)[O:70][CH2:69]2)[C:49](=[O:68])[N:50]3[CH3:55])=[CH:2]1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Reactant: OB(O)c1ccoc1
Agent: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: OB(O)c1cnc2ccccc2c1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(-c3ccoc3)cccc21

Procedure:
Following the procedure as described in EXAMPLE 2.46 and making non-critical variations using 3-furanboronic acid to replace quinolin-3-ylboronic acid, and 4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 4′-furan-3-yl-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (65%) as a colorless solid: mp 178-180° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.38-7.29 (m, 2H), 7.00 (d, J=7.9 Hz, 1H), 6.86 (d, J=7.8 Hz, 1H), 6.76 (s, 1H), 6.41 (s, 1H), 6.28 (s, 1H), 6.04-6.01 (m, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.53 (d, J=9.0 Hz, 1H), 4.23-4.09 (m, 4H), 3.26 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.0, 155.5, 144.7, 144.3, 142.8, 140.5, 137.9, 130.8, 129.1, 128.1, 125.2, 122.6, 122.5, 111.2, 111.1, 107.4, 99.7, 76.7, 64.6, 64.0, 58.3, 26.8; MS (ES+) m/z 375.9 (M+1).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([OH:30])=[CH:25][C:24]=3[Cl:31])=[O:15])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:35][CH2:36][OH:37]>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH2:35][CH2:36][OH:37])=[CH:25][C:24]=3[Cl:31])=[O:15])[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: OCCBr
Reactant: O=C(c1cnccc1Oc1cc(Cl)c(O)cc1Cl)N1CCN(C2CC2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cnccc1Oc1cc(Cl)c(OCCO)cc1Cl)N1CCN(C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
To a solution of 0.15 g (0.33 mmol) (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-4-hydroxy-phenoxy)-pyridin-3-yl]-methanone (Example 57) in 2 mL N,N-dimethylformamide was added 0.016 g (0.37 mmol) sodium hydride (60% dispersion in mineral oil, Aldrich). The reaction mixture was stirred for 15 min. at room temperature before 0.03 mL (0.36 mmol) 2-bromoethanol (commercially available, CAS RN 540-51-2) were added. After stirring for 3 hours at room temperature another 0.03 mL (0.36 mmol) 2-bromoethanole were added. After 72 hours the reaction mixture was poured on water and was extracted three times with ethyl acetate. The organic layers were washed with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 25:75) to give 0.075 g (46%) of the title compound as a light brown foam. MS (ESI): m/z=500.113 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][OH:10])[N:6]=[C:5]([CH2:11][OH:12])[N:4]=1.N1C=CC=CC=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>C(Cl)Cl>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([CH2:2][C:3]2[N:8]=[C:7]([CH2:9][OH:10])[N:6]=[C:5]([CH2:11][OH:12])[N:4]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: OCc1nc(CO)nc(CO)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Cc2nc(CO)nc(CO)n2)cc1
Reaction time: 8 h

Procedure:
2,4,6-Trihydroxymethyl-s-triazine (1 eq.) is dissolved in an excess of pyridine. p-Toluenesulfonylchloride (0.6 eq.) in CH2Cl2 is added and the reaction mixture is stirred overnight. The solvent volume is reduced to a slurry to which water and dichloromethane are added and the resulting mixture is extracted with CH2Cl2. The combined CH2Cl2 layers are dried (MgSO4) and concentrated to an oil. The oil is purified by silica gel flash column chromatography to give the title compound.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(C1CCN(C(=O)[C@H](NC(C2C3C(=NC=C(Br)N=3)N(COCC[Si](C)(C)C)C=2)=O)C2CC2)CC1)#N.[CH:67]1([CH2:70][O:71][C:72]2[CH:77]=[CH:76][N:75]=[C:74]([Sn](CCCC)(CCCC)CCCC)[CH:73]=2)[CH2:69][CH2:68]1.C(C1C=CN=C([Sn](CCCC)(CCCC)CCCC)C=1)(C)(C)C>>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:74]4[CH:73]=[C:72]([O:71][CH2:70][CH:67]5[CH2:68][CH2:69]5)[CH:77]=[CH:76][N:75]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(OCC2CC2)ccn1
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Agent: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Agent: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3cc(OCC4CC4)ccn3)nc12)C(=O)N1CC(C#N)C1

Procedure:
Prepared according to the procedure outlined in Example 111, steps 4-5 substituting 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide for 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide and 4-cyclopropylmethoxy-2-tributylstannanyl-pyridine for 4-tert-butyl-2-(tributylstannyl)pyridine. MS: (M+H)+=446.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([O:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=1)=[C:9]([C:30]1[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][C:31]=1[CH3:38])[CH:8]=[CH:7]2.B(Br)(Br)Br>ClCCl>[CH3:38][C:31]1[CH:32]=[C:33]([S:36][CH3:37])[CH:34]=[CH:35][C:30]=1[C:9]1[C:10]([O:14][C:15]2[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:4]([OH:3])[CH:13]=[CH:12]2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(SC)cc3C)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CSc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)c(C)c1
Temperature: 5 °C
Yield: 99.9 %

Procedure:
Dissolve 1-(2-{4-[6-methoxy-2-(2-methyl-4-methylsulfanyl-phenyl)-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine hydrochloride (331 mg, 0.603 mmol) in dichloromethane (15 mL) and cool to 5° C. Add BBr3 (285 μL, 3.02 mmol) to the light suspension over 5 minutes. Quench the reaction after 1 hour with saturated aqueous NaHCO3 (15 mL). Separate the layers and extract the aqueous layer with dichloromethane (2×10 mL). Pour the solution onto a SiO2 plug (20 g) and elute with methanol in dichloromethane (5 to 15%). Concentrate the fractions in vacuo to give 301 mg of the title compound (100%): mass spectrum (ion spray) m/z=500.3 (M+H).
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][CH2:16][C:17]1[C:18]([F:34])=[C:19]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:28]#[N:29])[C:20]([Br:23])=[CH:21][CH:22]=1.[Cl:35][C:36]1[N:37]=[C:38]([CH2:52][O:53][Si](C(C)(C)C)(C)C)[N:39](COCC[Si](C)(C)C)[C:40]=1[C:41](O)=[O:42].C(=O)(O)[O-].[Na+].FC(F)(F)C(O)=O>CN(C=O)C>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:41]([C:40]2[NH:39][C:38]([CH2:52][OH:53])=[N:37][C:36]=2[Cl:35])=[O:42])=[C:18]([F:34])[C:19]=1[O:24][C:25]1[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(Cl)c(C(=O)O)n1COCC[Si](C)(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CNC(=O)c3[nH]c(CO)nc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
EDC (0.025 g, 0.131 mmol) and HOBT (0.018 g, 0.131 mmol) were added to a solution of 3-{[3-(aminomethyl)-6-bromo-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.042 g, 0.119 mmol) and 4-chloro-2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.050 g, 0.119 mmol) in DMF (2 mL). The mixture was stirred at RT for 4 hrs, saturated sodium bicarbonate was added and the solution was extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. The crude product was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.3 mL, 3.89 mmol) was added. The mixture was stirred at RT overnight. The solvent was evaporated and the residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% formic acid) to give the title compound (0.030 g, 47%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.99 (br. s., 1H), 8.32-8.41 (m, 1H), 7.79-7.84 (m, 1H), 7.57-7.65 (m, 1H), 7.47-7.52 (m, 1H), 7.44 (t, 1H), 7.31 (t, 1H), 5.54 (br. s., 1H), 4.45-4.53 (m, 2H), 4.37-4.44 (m, 2H). ES MS: m/z 512, 514.
Reaction SMILES: B(O)(O)[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]([CH3:31])=[C:21]([CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[CH3:30])[N:22]=2)=[CH:14][CH:13]=1>>[CH3:31][C:20]1[O:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)=[CH:13][CH:14]=2)=[N:22][C:21]=1[CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH3:30]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Product: Cc1ccc(-c2ccc(-c3nc(CCN4CCC[C@H]4C)c(C)o3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from tolyl boronic acid (195 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 33 mg (32%). MS (m/e) 361.3 (M+1)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([Cl:14])[N:9]=2)[N:5]=[CH:4][N:3]=1.[NH2:15][CH:16]1[CH2:20][O:19][CH2:18][CH2:17]1.O1CCC[CH2:22]1>>[Cl:14][C:10]1[N:9]=[C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:15][CH:16]3[CH2:17][CH2:18][O:19][CH2:22][CH2:20]3)[N:7]=2)[CH:13]=[CH:12][N:11]=1
Reactant: C1CCOC1
Reactant: Clc1nccc(-c2ncnc(Cl)n2)n1
Reactant: NC1CCOC1
Product: Clc1nccc(-c2ncnc(NC3CCOCC3)n2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of 2-chloro-4-(2-chloro-4-pyrimidinyl)-1,3,5-triazine (i.e., the product of Example 1, Step B) (290 mg, 1.27 mmol) in tetrahydrofuran (20 mL) was added 4-aminotetrahydrofuran (284 mg, 2.8 mmol). The resulting mixture was stirred at room temperature overnight and then concentrated and purified using column chromatography on silica gel eluted with 60% ethyl acetate in hexanes to give 300 mg of the title compound as a white solid.