Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11].C(O)(=O)C.[Br:17]Br>ClCCl>[Br:17][C:8]1[C:9]([OH:10])=[C:4]([C:5]([OH:11])=[CH:6][CH:7]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: BrBr
Reactant: COC(=O)c1c(O)cccc1O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1c(O)ccc(Br)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a mixture of methyl-2,6-dihydroxybenzoate (1.68 g, 10.0 mmol) in dichloromethane (10 mL) was added acetic acid (1 mL), followed by drop-wise addition of bromine (515 μL, 10.0 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at ambient temperature for 1 hour, concentrated under reduced pressure, co-evaporated with ethyl acetate (2×). The resulting solid was triturated with hexane/ethyl acetate and re-crystallized from hot hexane/ethyl acetate to provide the titled compound (1.45 g). MS ESI(−,) m/e 244, 246 (M−H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 10.19 (s, 1H), 7.46 (d, 1H), 6.41 (d, 1H), 3.84 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][C:16](OCC)=[O:17])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCc1oc(-n2ccnc2C)nc1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nccn1-c1nc(-c2ccc(F)cc2)c(CCCCO)o1
Reaction time: 1 h

Procedure:
Ethyl 4-(4-fluorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanoate (2.31 g) was dissolved in 20 ml of tetrahydrofuran, to which was added gradually lithium aluminum hydride (269 mg) under ice-cooling. The resulting mixture was stirred for 1 hour. Water (0.5 ml) was carefully added to the reaction mixture. The resulting mixture was filtered, and the residue on the filter paper was washed with ethyl acetate. The filtrate was concentrated to give crystals of 4-(4-fluorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanol. Recrystallization from ethyl acetate gave pale yellow prisms (885 mg, 47%). Melting point 97-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=[O:13])[N:10]([CH2:14][C:15]([NH:17][C:18]([CH3:30])([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH3:19])=[O:16])[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:37][C:38]([F:43])([F:42])[CH:39]1[O:41][CH2:40]1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:40][CH:39]([OH:41])[C:38]([F:43])([F:42])[F:37])[C:11](=[O:13])[N:10]([CH2:14][C:15]([NH:17][C:18]([CH3:30])([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[CH3:19])=[O:16])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)[nH]c1=O)c1cccc(C(F)(F)F)c1
Reactant: FC(F)(F)C1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
3.61 g (8.23 mmol) of 2-[3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}-acetamide from Example 241A are dissolved in 20 ml of DMF with 3.75 g (11.52 mmol) of caesium carbonate and treated with 2.22 g (11.52 mmol) of 1,1,1-trifluoro-2,3-epoxypropane. This is stirred for 2.5 hrs at 75° C. The suspension is then diluted with 30 ml of ethyl acetate and washed twice with 20 ml water each time. The organic phase is dried over sodium sulphate and filtered. After concentration, the crude product is purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate first 5:1, then 1:1). 3.14 g (69% of theory) of the target compound are thus obtained.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10]([OH:12])=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:81][C:82]([N:84]1[CH2:88][CH2:87][CH:86]([NH2:89])[CH2:85]1)=[O:83])[CH2:78][CH2:79][CH3:80]>CN(C=O)C.C(OCC)(=O)C>[CH2:77]([O:81][C:82]([N:84]1[CH2:88][CH2:87][CH:86]([NH:89][C:10](=[O:12])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:5])=[O:43])[CH2:85]1)=[O:83])[CH2:78][CH2:79][CH3:80]
Reactant: CCCCOC(=O)N1CCC(N)C1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCC(NC(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)C1
Reaction time: 12 h

Procedure:
To a solution of 303 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 34 μl DIPEA, 193 mg HATU and 103 mg 3-amino-pyrrolidine-1-carboxylic acid butyl ester. After stirring for 12 h the reaction mixture was diluted with ethyl acetate, washed with aqueous LiCl (4%) and saturated NaHCO3 solution. The solution was concentrated, dissolved in dichloromethane and stirred in the presence of 384 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 290 mg MS (ES+): m/e=710.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]([OH:15])=O>CS(O)(=O)=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]2[C:4]=1[CH2:11][CH2:12][C:13]2=[O:15]
Reactant: COc1cccc(CCC(=O)O)c1OC
Agent: CS(=O)(=O)O
Product: COc1ccc2c(c1OC)CCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
Under nitrogen a solution of 3-(2,3-dimethoxyphenyl)-propanoic acid (2 g) in 50 ml methanesulfonic acid was warmed at 60° C. and kept there for 2 hours. The reaction mixture was cooled to room temperature and poured into ice/water. After extraction with ethyl acetate the organic layer was washed with a 1N aqueous sodium hydroxyde solution, dried over magnesium sulfate, filtered and evaporated in vacuo yielding 1.2 g of 2,3-dihydro4,5-dimethoxy-1H-inden-1-one, M.S. (C.I.) (M/Z): 193 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:20])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[CH3:21][C:22]1[CH:35]=[CH:34][C:25]([CH2:26][C:27]2([OH:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:20])[CH2:2][N:30]2[CH2:31][CH2:32][C:27]([CH2:26][C:25]3[CH:24]=[CH:23][C:22]([CH3:21])=[CH:35][CH:34]=3)([OH:33])[CH2:28][CH2:29]2)=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Reactant: OC(CCl)COc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1ccc(CC2(O)CCN(CC(O)COc3ccc(OCc4ccccc4)cc3)CC2)cc1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
A mixture of (RS)-1-chloro-3-[4-(benzyloxy)phenoxy]-2-propanol (1.0 g, 3.4 mmol), 4-(4-methyl-benzyl)-piperidin-4-ol (0.70 g, 3.4 mmol) and potassium carbonate (0.50 g, 3.6 mmol) in 2-butanone was refluxed for 2 days. It was cooled to room temperature, 50 ml of H2O were added and the organic phase was separated. The water phase was extracted two times with ethyl acetate. The organic phases were then pooled, dried with Na2SO4 and the solvent evaporated. The residue was chromatographed over silica gel (CH2Cl2 --MeOH, 98:2) to give (RS)-1-[3-(4-benzyloxy-phenoxy)-2-hydroxy-propyl]-4-(4-methyl-benzyl)-piperidin-4-ol as a colorless solid (0.75 g, 48%). MS: m/e=462.5 (M+H+)
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[N:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[N:34]1.C1(C)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CO.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>[CH3:26][O:25][CH2:24][CH2:23][O:22][C:3]1[C:2]([C:37]2[N:33]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][O:27]3)[N:34]=[CH:35][CH:36]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: COCCOc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COCCOc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1ccnn1C1CCCCO1
Reaction time: 0.25 h

Procedure:
A mixture of 5-bromo-6-(2-methoxyethoxy)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 51.1, 50 mg, 0.115 mmol), 1-(tetrahydro-2h-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (49 mg, 0.172 mmol), Pd(Ph3P)4 (13 mg, 0.011 mmol) and toluene (0.5 mL) was stirred for 15 min under an argon atmosphere. K3PO4 (73 mg, 0.345 mmol) was added and the RM was stirred at 110° C. for 6 h. The RM was diluted with MeOH, filtered through a cartridge of PL-Thiol MP-Resin, and the filtrate was evaporated to dryness under reduced pressure to afford 6-(2-methoxyethoxy)-5-(1-(tetrahydro-2h-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, of which (50 mg, 0.099 mmol), TFA (0.25 mL, 3.24 mmol) and DCM (0.4 mL) was stirred at RT for 2 h. The mixture was treated with a solution of Na2CO3 (2 M) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative SFC (Column Diol; gradient 13% to 18% in 6 min.) and lyophilized to afford an off-white powder. UPLC-MS (Condition 2) tR=1.04 min, m/z=423.3 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 3.34 (s, 3H) 3.73-3.82 (m, 2H) 4.58 (br. s, 2H) 6.90 (d, J=1.88 Hz, 1H) 7.37 (d, J=8.47 Hz, 2H) 7.83-7.87 (m, 1H) 7.89 (d, J=9.03 Hz, 2H) 8.70 (d, J=2.26 Hz, 1H) 8.77-8.90 (m, 1H) 10.55 (br. s, 1H) 13.06-13.22 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:4]=1[NH:5][C:6](=[O:16])[CH2:7][C:8](=[O:15])[C:9]([S:12][CH2:13][CH3:14])([CH3:11])[CH3:10].C([O-])(=O)C.[Na+].[C:29]([C:34]1[CH:46]=[C:45]([C:47]([CH2:50][CH3:51])([CH3:49])[CH3:48])[CH:44]=[CH:43][C:35]=1[O:36][CH:37]([CH2:41][CH3:42])[C:38](Cl)=[O:39])([CH2:32][CH3:33])([CH3:31])[CH3:30]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]([NH:21][C:38](=[O:39])[CH:37]([O:36][C:35]2[CH:43]=[CH:44][C:45]([C:47]([CH2:50][CH3:51])([CH3:49])[CH3:48])=[CH:46][C:34]=2[C:29]([CH2:32][CH3:33])([CH3:31])[CH3:30])[CH2:41][CH3:42])=[CH:17][C:4]=1[NH:5][C:6](=[O:16])[CH2:7][C:8](=[O:15])[C:9]([S:12][CH2:13][CH3:14])([CH3:11])[CH3:10]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Cl
Reactant: CCSC(C)(C)C(=O)CC(=O)Nc1cc([N+](=O)[O-])ccc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCSC(C)(C)C(=O)CC(=O)Nc1cc(NC(=O)C(CC)Oc2ccc(C(C)(C)CC)cc2C(C)(C)CC)ccc1OC
Temperature: 90 °C
Yield: 75 %

Procedure:
A mixture of 82 g of 2'-methoxy-5'-nitro-(2-ethylthio-2methylpropionyl)acetanilide obtained in Synthesis Example 3 and 800 ml of glacial acetic acid was heated to 90° C. To the mixture, 80 g of reduced iron was gradually added over a four minute period under a nitrogen atmosphere and with stirring. The reaction mixture was cooled to room temperature, and 24.1 g of sodium acetate and then 97 g of 2-(2,4-di-tert-amylphenoxy)butyryl chloride were added, and the mixture was stirred vigorously for 1 hour. The reaction mixture was filtered to remove the insoluble substances. The filtrate was poured into 1 liter of ethyl acetate, washed 4 times, each with 1 liter of a saturated aqueous sodium chloride solution, and then dried with sodium sulfate. After distilling off ethyl acetate, the residue was recrystallized from ethanol to obtain 110 g (yield 75%) of Coupler (13) having a melting point of 65° to 67° C.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:15]([NH:18][CH:19]=O)([CH3:17])[CH3:16].P(Cl)(Cl)(Cl)=O>>[CH:15]([N:18]=[CH:19][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)([CH3:17])[CH3:16]
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Reactant: CC(C)NC=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N=CN1c2ccccc2Cc2ccccc21

Procedure:
Reaction of acridan, isopropylformamide and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-[(ISOPROPYLIMINO)METHYL]ACRIDAN, m.p. 149.5-150.5° C. (corr.), from n-hexane.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([CH2:27][S:28]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([CH2:27][S:28]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC(Oc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1CS(=O)(=O)c1cccc2ccccc12
Temperature: 75 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A solution of 4-[3-(1-naphthylsulfonylmethyl)-4-nitrophenoxy]piperidin-1-ylcarboxylic acid benzyl ester (3.90 g, 6.96 mmol) in ethyl acetate was treated sequentially with ethanol and tin (II) chloride dihydrate (24.0 g, 106 mmol), stirred at 75° C. under nitrogen for 3 hours and concentrated in vacuo. The resultant residue was partitioned in ethyl acetate and water. The phases were separated; the organic phase was washed with 2.5 N sodium hydroxide and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo for 20 minutes at 78° C. to yield 4-[4-amino-3-(naphthalene-1-sulfonylmethyl)-phenoxy]-piperidine-1-carboxylic acid benzyl ester as a dark yellow film, 3.3 g (89% yield), Mass spectrum (+EI, [M+H]+) m/z 531. 1HNMR (500 MHz, DMSO-d6): δ8.57 (d, 1H, J=8.54 Hz), 8.24 (d, 1H, J=8.17 Hz), 8.03-8.06 (m, 1H), 8.00 (dd, 1H, J=7.44 Hz and 1.22 Hz), 7.58-7.69 (m, 3H), 7.27-7.38 (m, 5H), 6.53-6.58 (m, 2H), 5.97 (d, 1H, J=2.56 Hz), 5.04 (s, 2H), 4.71 (s, 2H), 4.64 (s, 2H), 3.61-3.66 (m, 1H), 3.47-3.53 (m, 2H), 2.99-3.05 (m, 2H), 1.43-1.48 (m, 2H), 1.10-1.19 ppm (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:37]1[CH:42]=[N:41][CH:40]=[CH:39][N:38]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:37]4[CH:42]=[N:41][CH:40]=[CH:39][N:38]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Brc1cnccn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2cnccn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromopyrazine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.157, m/z=458; 1H NMR (CDCl3) 1.31 (m, 1H), 1.52 (d, 3H), 1.63 (m, 1H), 1.81-1.95 (m, 2H), 2.09-2.32 (m, 3H), 2.91 (m, 1H), 3.68 (t, 2H), 5.69 (m, 1H), 6.91 (m, 4H), 7.21 (m, 2H), 7.73 (m, 2H), 8.43 (s, 1H), 8.56 (s, 1H), 8.89 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.[Li]C(CC)C.C(Br)(Br)(Br)[Br:27]>C1COCC1>[Br:27][C:7]1[C:2]([Cl:1])=[C:3]2[CH:10]=[CH:9][N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[C:4]2=[N:5][CH:6]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Reactant: BrC(Br)(Br)Br
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(Br)cnc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
4-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyri dine (0.55 g, 1.78 mmol) was dissolved in THF (15 mL) and cooled to −78° C. s-BuLi (2.80 mL, 3.92 mmol) was then added dropwise. The solution was then stirred at −78° C. for 30 minutes. CBr4 (1.48 g, 4.45 mmol) was then added as a THF (2 mL) solution. The reaction was stirred for an additional 30 minutes as it was allowed to warm to 0° C. The reaction was then quenched with saturated NH4Cl and allowed to warm to room temperature. The reaction was then extracted with DCM (3×50 mL), dried, and filtered to give a crude residue. The crude residue was purified by chromatography with hexane to give 5-bromo-4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (0.502 g, 72.7% yield).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Si](C)(C)[N:14]1[C:18]2=[N:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:22]=[C:17]2[C:16]([C:30](O)=[O:31])=[CH:15]1)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([NH:8][C:30]([C:16]1[C:17]2[C:18](=[N:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:22]=2)[NH:14][CH:15]=1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)n1cc(C(=O)O)c2cc(-c3cccc(F)c3)cnc21
Reactant: NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)c1c[nH]c2ncc(-c3cccc(F)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To a solution of benzylamine (4.4 μL, 40.3 μmol) in dry CH2Cl2 (0.5 mL) was added carboxylic acid 10 (15 mg, 40.5 μmol), WSCHCl (9.32 mg, 44.86 μmol), HOBT (5.5 mg, 40.5 μmol) and i-Pr2NEt (7.1 μL, 40.8 μmol) and the reaction mixture left to stir at r.t. overnight Separation by LCMS (CombiPrep ODS-AM column) using water—acetonitrile as eluent (in gradient) afforded amide 11 (2.33 mg, 17%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.70 (d, J=5.5 Hz, 2H), 6.18 (t, J=5.5 Hz, 1H), 7.29-7.44 (m, 8H), 7.80 (s, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.66 (d, J=2.1 Hz, 1H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:22])([CH3:21])[C:14]([NH:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])=[CH:9][C:8]=1[CH3:23])(=O)=O.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:17]([NH:16][C:14](=[O:15])[C:13]([CH3:22])([C:10]1[CH:11]=[CH:12][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:8]([CH3:23])[CH:9]=1)[CH3:21])[CH:18]([CH3:20])[CH3:19]
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(C(C)(C)C(=O)NCC(C)C)ccc1OS(=O)(=O)C(F)(F)F
Product: Cc1cc(C(C)(C)C(=O)NCC(C)C)ccc1-c1ccccc1
Yield: 75 %

Procedure:
Prepared in a similar manner to Example 1 from 4-(1-(isobutylamino)-2-methyl-1-oxopropan-2-yl)-2-methylphenyl trifluoromethanesulfonate (example 50a) and phenyl boronic acid. Yield: 75%. 1H NMR (400 MHz, dMSO): δ 0.76-0.77 (d, 6H), 1.46 (s, 6H), 1.72-1.73 (m, 1H), 2.21 (s, 3H), 2.84-2.87 (m, 2H), 7.13-7.21 (m, 3H), 7.30-7.37 (m, 4H), 7.41-7.45 (m, 2H); MS+H (310).
Reaction SMILES: [N+]([O-])(O)=O.[CH3:5][C:6]1[NH:11][C:10](=[O:12])[NH:9][CH:8]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:7]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:5][C:6]1[NH:11][C:10](=[O:12])[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:7]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C1=C(C)NC(=O)NC1c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(C)cc2)nc(=O)[nH]c1C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a cold (0° C.) mixture of nitric acid (70%) (34 ml) and water (6 mL) was added ethyl 6-methyl-2-oxo-4-p-tolyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (6 g; 21,87 mmol) in small portions (within 3 min). The mixture was stirred for 30 min while gradually allowed to reach room temperature. The reaction was poured onto crushed ice and neutralized by adding potassium carbonate until pH 8. The aqueous layer was extracted with chloroform (3 times) and the combined organics were dried over sodium sulphate, filtered and concentrated under reduced pressure. The obtained green oil was dissolved in dichloromethane and concentrated under reduced pressure to afford a green solid, which was crystallized from ethanol and the obtained greenish crystals were triturated with heptane to furnish 3.7 g (60%) of the title compound as a white-to-green solid.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][C:15]1[C:20]([CH2:21][OH:22])=[CH:19][CH:18]=[C:17]([CH3:23])[N:16]=1.[CH2:24]([O:26][C:27](=[O:39])[CH2:28][C:29]1[C:33]2[CH:34]=[CH:35][C:36](O)=[CH:37][C:32]=2[S:31][CH:30]=1)[CH3:25].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH2:24]([O:26][C:27](=[O:39])[CH2:28][C:29]1[C:33]2[CH:34]=[CH:35][C:36]([O:22][CH2:21][C:20]3[C:15]([CH3:14])=[N:16][C:17]([CH3:23])=[CH:18][CH:19]=3)=[CH:37][C:32]=2[S:31][CH:30]=1)[CH3:25]
Reactant: Cc1ccc(CO)c(C)n1
Reactant: CCOC(=O)Cc1csc2cc(O)ccc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a mixture of tri-n-butylphosphine (7.10 mL), (2,6-dimethylpyridin-3-yl)methanol (3.00 g), ethyl(6-hydroxy-1-benzothiophen-3-yl)acetate (5.43 g) and THF (150 mL) was added ADDP (7.17 g) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere overnight. The mixture was concentrated. To the residue was added IPE and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (7.74 g)