Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].CC(C)=O.[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:19]=1[I:25]>O>[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[C:22]([O:24][CH2:2][CH2:3][CH3:4])[CH:21]=[CH:20][C:19]=1[I:25]
Reactant: CCCBr
Reactant: COC(=O)c1cc(O)ccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCOc1ccc(I)c(C(=O)OC)c1
Reaction time: 0.5 h

Procedure:
2.97 mL (32.7 mmol) 1-bromopropane and 299 mg (1.80 mmol) KI are added to a mixture of 3.39 g (24.5 mmol) K2CO3 and 200 mL acetone. The mixture is stirred for 30 min at reflux. Subsequently, 5.00 g (18.0 mmol) methyl-5-hydroxy-2-iodobenzoate are added and the resulting mixture is refluxed for 2 h. One additional equivalent of 1-bromopropane and of K2CO3 is added and refluxing is continued for 12 h. Water is added and the mixture is extracted with EtOAc. The organic layer is dried over sodium sulphate and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, heptane/EtOAc 100/0→60/40). The product is used without further characterization.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[C:8](Cl)=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:15](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.CCOCC>[C:1]([C:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[C:8]([CH3:15])=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1ncc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 77.4 %

Procedure:
To a solution of 5-tert-butyl-2-chloro-3-nitro-pyridine (554 mg, 2.58 mmol) dissolved in 10% aqueous dioxane (5.0 mL) was added potassium carbonate (1.07 g, 7.74 mmol), trimethylboroxine (395 mL, 2.84 mmol), and lastly tetrakis-(triphenylphosphine)palladium (149 mg, 0.129 mmol). The solution was heated in a sealed tube to 100° C. for 18 h, cooled to room temperature and diluted with ether. The organic layer was washed twice with saturated aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica-gel chromatography (10% ethyl acetate in hexane) provided 5-tert-butyl-2-methyl-3-nitro-pyridine (388 mg, 75%) as colorless oil.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=3)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[C:1]1([N:7]2[CH:11]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3ccccc3)nn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cn(-c3ccccc3)nn2)CC1
Yield: 99.4 %

Procedure:
tert-Butyl 4-[1-phenyl-1H-[1,2,3]triazol-4-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (5 mg) was dissolved in 1 ml of ethanol, a catalytic amount of 20% palladium hydroxide was added and the mixture was vigorously stirred for 30 minutes in a hydrogen atmosphere. The reaction solution was filtered through Celite. The solvent was evaporated from the resulting filtrate to give 5 mg of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:68]([C:72]([C:78]([OH:80])=[O:79])([CH2:74][CH2:75][CH2:76][CH3:77])[NH2:73])[CH2:69][CH2:70][CH3:71]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[O:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:73][C:72]([CH2:74][CH2:75][CH2:76][CH3:77])([C:78]([OH:80])=[O:79])[CH2:68][CH2:69][CH2:70][CH3:71])=[O:35])=[O:31])=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: CCCCC(N)(CCCC)C(=O)O
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCC(CCCC)(NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reaction time: 1 h
Yield: 34.3 %

Procedure:
N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.020 g, 0.037 mmol) and NMM (0.040 ml, 0.363 mmol) were dissolved in DCM (5 ml) at 30° C. TBTU (a total of 0.016 g, 0.050 mmol) were added in portions and the mixture was stirred for 1 h. 2-Butylnorleucine (0.007 g, 0.037 mmol) was added and the mixture was stirred at 30° C. for 18 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC, using a gradient of 20-50% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.009 g (34% yield) of the title product was obtained as a white solid. M/z: 710.1. 1H NMR (DMSO, 400 MHz): δ 0.73-0.82 (m, 6H), 0.88-1.22 (m, 8H), 1.56-1.69 (m, 2H), 1.96-2.07 (m, 2H), 3.71 (d, 2H), 4.32 (d, 1H), 4.36 (ABq, 2H), 4.52 (s, 2H), 5.16 (d, 1H), 6.95-7.01 (m, 2H), 7.11-7.26 (m, 4H), 7.30-7.40 (m, 4H), 7.61 (s, 1H), 7.98-8.06 (m, 2H), 8.25-8.42 (m, 1H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([OH:28])C>[OH-].[K+]>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]2[N:1]=[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]3=[C:4]([C:2]([OH:28])=[O:3])[C:21]=2[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCc2nc3ccccc3c(C(=O)O)c2C1
Yield: 29 %

Procedure:
Isatin (14.71 g, 100 mmol) and 1-t-butoxycarbonyl-4-piperidone (19.93 g, 100 mmol) were dissolved in ethanol (200 ml), followed by adding thereto an ethanolic solution (50 ml) of KOH (12.34 mg), and the resulting mixture was stirred at 70° C. for 24 hours. The solvent was removed by concentration under reduced pressure, and the residue was neutralized with acetic acid. The resulting insoluble material was purified by suspension in methanol to obtain the desired compound (9.5 g, 29%) as a light-brownish-white substance.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:24][C:25]1[N:29]2[N:30]=[C:31](Cl)[CH:32]=[CH:33][C:28]2=[N:27][C:26]=1[C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37].C(=O)(O)[O-].[Na+]>>[ClH:24].[ClH:24].[ClH:24].[Cl:24][C:25]1[N:29]2[N:30]=[C:31]([NH:17][CH2:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][N:8]([CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:13][CH2:12]3)[CH:32]=[CH:33][C:28]2=[N:27][C:26]=1[C:35]([CH3:41])([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)c1nc2ccc(Cl)nn2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)c1nc2ccc(NCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)nn2c1Cl
Product: Cl
Yield: 129.8 %

Procedure:
1.75 g of 4-(diphenylmethyl)-1-piperazinepropanamine and 854 mg of ethyl 2-[3,6-dichloroimidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate were stirred at 160° C. for 4 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol (30:1). The desired fraction was collected, concentrated under reduced pressure and dissolved in 5 ml of ethyl acetate; 1.55 ml of a 4 N solution of hydrogen chloride in ethyl acetate was added, followed by concentration again. The crystal precipitated was washed by the addition of ethanol-ethyl acetate (1:3), collected by filtration and dried to yield 628 mg of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CS(C)=O.CCOC(C)=O>[CH2:10]([NH:9][C:7]([CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: NC(=O)C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(NCc1ccccc1)C1CCNCC1
Yield: 34.7 %

Procedure:
4-Piperidinecarboxamide (10.2 g, 78.0 mmol) in DMSO (10 mL) was treated with benzyl bromide (20.0 mL, 168 mmol). The mixture was diluted with EtOAc and washed with 1N aq. HCl, 5N aq. NaOH, dried over MgSO4, and concentrated to give 5.90 g (35%) of N-benzyl-4-piperidinecarboxamide. [1H]-NMR(CDCl3) consistent with structure.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:16]([O:18]C)=[O:17])[CH:11]=2)[O:6][C:5]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>CO.C1COCC1.CCOC(C)=O>[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:16]([OH:18])=[O:17])[CH:11]=2)[O:6][C:5]=1[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(C)c(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1-c1cnc2oc(-c3ccc(F)cc3)c(Br)c2c1
Reaction time: 1 h
Yield: 96.6 %

Procedure:
NaOH (3.3 mL, 3.3 mmol, 1M aq) was added to a stirring solution of methyl 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (294 mg, 0.668 mmol) in MeOH (7 mL) and THF (7 mL) at 60° C. It was allowed to stir for 1 hr. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoic acid (275 mg, 0.645 mmol, 97% yield) consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.90 (1H, br. s.), 8.40 (1H, d, J=2.26 Hz), 8.18-8.25 (2H, m), 8.05 (1H, d, J=2.26 Hz), 7.92 (1H, dd, J=7.78, 1.76 Hz), 7.85 (1H, d, J=1.76 Hz), 7.43-7.54 (3H, m), 2.35 (3H, s). LC-MS retention time: 2.42 min; m/z (MH+): 426, 428. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([C:20]#[C:21][CH:22]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[OH:23])[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][CH2:9][C:10]1([C:20]#[C:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[O:23])[CH2:11][CH2:12][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:18][CH2:19]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(O)C#CC2(COCc3ccccc3)CCC3(CC2)OCCO3)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccc(C(=O)C#CC2(COCc3ccccc3)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 92.4 %

Procedure:
To a solution of 3-(8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyppropyn-1-ol (Reference Example 88) (585 mg, 1.44 mmol) in dichloromethane (7.2 mL), manganese dioxide (625 mg, 7.19 mmol) was added, and the obtained solution was stirred at room temperature for 13 hours. The reaction solution was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (540 mg, 1.33 mmol, 93%) as a colorless oily compound.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[C:33](O)(=[O:37])[C@@H:34]([CH3:36])[OH:35].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>C(Cl)Cl.CN(C=O)C>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:33](=[O:37])[C@H:34]([OH:35])[CH3:36])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: C[C@@H](O)C(=O)O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)[C@@H](C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 8-azetidin-3-ylmethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (57 mg, 0.13 mmol), D-lactic acid (14 mg, 0.16 mmol) and DIPEA (27 μL, 0.16 mmol) in DCM (2 mL) and DMF (1.5 mL) was added HATU (60 mg, 0.16 mmol). The resulting yellow mixture was stirred for 2 h at r.t. then partitioned between DCM and H2O. The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) followed by Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 679 as a cream foam (23 mg, 35%). LCMS: RT 2.92 min, [M+H]+ 505.2. 1H NMR (CDCl3, 400 MHz): δ 8.00-7.98 (1 H, m), 7.81-7.70 (1 H, m), 7.26 (2 H, s), 4.49-4.20 (7 H, m), 3.91 (1 H, dd, J=10.38, 5.67 Hz), 3.86 (5 H, t, J=4.71 Hz), 3.76-3.75 (3 H, m), 3.36-3.35 (4 H, m), 3.18-3.15 (2 H, m), 1.44 (3 H, t, J=7.46 Hz), 1.34 (3 H, dd, J=6.68, 4.79 Hz)
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[C:10]([C@@H:12]([NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH2:13][CH:14]=[CH2:15])[CH:9]=[CH:8][N:7]=1)(=[O:5])=[O:4])[CH3:2]>CO.[Pd]>[CH2:1]([S:3]([C:6]1[CH:11]=[C:10]([C@@H:12]([NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][N:7]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: C=CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(=O)(=O)CC)c1
Agent: [Pd]
Solvent: CO
Product: CCC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(=O)(=O)CC)c1
Reaction time: 0.33 h

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid[(S)-1-(2-ethanesulfonyl-pyridin-4-yl)-but-3-enyl]-amide (136 mg, 0.284 mmol) in MeOH (30 mL) was hydrogenated over 10% Pd/C using a continuous flow hydrogenation apparatus (conditions: full H2 mode, flow rate 1 mL/minute, 30° C., 1 atmosphere). The solution was concentrated in vacuo and purified by reversed-phase HPLC using a 20 minute gradient of 5-95% acetonitrile (0.1% TFA) in water (0.1% TFA) (flow rate=25 mL/min). The desired fractions were combined, neutralized with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford the title compound as an off white solid.
Reaction SMILES: [Cl:1][C:2]([CH3:25])([CH3:24])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([Cl:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[O:4].[Br:26]Br>ClC1C=CC=CC=1Cl>[Br:26][CH:11]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([Cl:22])([CH3:20])[CH3:21])=[CH:14][CH:13]=1)[C:8]1[CH:7]=[CH:6][C:5]([C:3](=[O:4])[C:2]([Cl:1])([CH3:25])[CH3:24])=[CH:10][CH:9]=1
Reactant: BrBr
Reactant: CC(C)(Cl)C(=O)c1ccc(Cc2ccc(C(=O)C(C)(C)Cl)cc2)cc1
Solvent: Clc1ccccc1Cl
Product: CC(C)(Cl)C(=O)c1ccc(C(Br)c2ccc(C(=O)C(C)(C)Cl)cc2)cc1
Temperature: 150 °C

Procedure:
A 350 ml sulfonation flask fitted with stirrer, reflux condenser and pressure equalized dropping funnel is charged with 2-chloro-1-{4-[4-(2-chloro-2-methyl-propionyl)-benzyl]-phenyl}-2-methyl-propan-1-one (113.1 g, 0.3 mol) and ortho-dichlorobenzene (150 ml). The mixture is heated to 150° C., and then a solution of bromine (49.6 g, 0.3 mol) in ortho-dichlorobenzene (50 ml) is added slowly in such a way that the bromine is reacted before the addition of the next drop of the bromine solution. When all the bromine has been added, the mixture is kept at 150° C. for another ten minutes, and then the ortho-dichlorobenzene is carefully removed on the rotavapor. The residue is recrystallized from hexanes to give the product (116.3 g, 85% of theory) as off white crystals, mp.=93° C. 1H-NMR (CDCl3, 400 MHz) δ 1.89 (s, 12 H, CH3); 6.29 (s, 1 H, CH); 7.54 (m, 4 H, H-4); 7.73 (m, 4 H, H-3). 13C-NMR (CDCl3, 100 MHz) δ 30.47 (C-8); 52.82 (C-1), 68.30 (C-7) 128.22 (C-3), 130.57 (C-4), 134.19 (C-5); 144.54 (C-2); 198.26 (C-6).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:15][CH2:14][CH2:13][CH2:12][N:10]2[CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[CH:9]2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NCCCn1cnc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCn1cnc(-c2ccccc2)c1)c1ccc(Br)cc1

Procedure:
A mixture of 2.0 g. of 4-phenyl-1H-imidazole-1-propanamine, 50 ml. of methylenechloride and 10 ml. of 1N sodium hydroxide was stirred and 2.2 g. of 4-bromobenzoyl chloride was added. The mixture was stirred for eighteen hours, methylene chloride was added and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was washed onto a filter with ether, giving the desired product, m.p. 132°-135° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:21]([O:23][CH3:24])=[O:22].[ClH:25]>O1CCOCC1>[ClH:25].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1F
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc(C2CCNCC2)ccc1F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
tert-Butyl 4-[4-fluoro-3-(methoxycarbonyl)phenyl]piperidine-1-carboxylate (471 mg, 1.40 mmol) was dissolved in anhydrous 4N HCl in dioxane (5 mL) and stirred at rt for 40 min. The reaction mixture was concentrated to afford methyl 2-fluoro-5-piperidin-4-ylbenzoate hydrochloride which was used without further purification. ESI-MS calc. for C13H16FNO2: 237; Found: 238 (M+H).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C@@H:21]4[CH2:26][CH2:25][C@H:24]([CH:27]=[N:28]O)[CH2:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.N1C=CC=CC=1.C1(S(Cl)(=O)=O)C=CC=CC=1>CC#N.O>[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[CH:17]=[N:18][N:19]([C@@H:21]3[CH2:22][CH2:23][C@H:24]([C:27]#[N:28])[CH2:25][CH2:26]3)[CH:20]=2)=[N:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](C=NO)CC4)c3)ncnc21
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: N#C[C@H]1CC[C@@H](n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Temperature: 25 °C
Yield: 109.5 %

Procedure:
[A] cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexanecarbaldehyde oxime (11.0 mg, 0.0000250 mol) was dissolved in pyridine (0.25 mL, 0.0031 mol), and benzenesulfonyl chloride (10.0 μL, 0.0000784 mol) was added and the resulting mixture was stirred at rt. After stirring 15 h, LCMS analysis showed formation of the product, M+H 423. The product was isolated by prep HPLCMS using a 19 mm×100 mm C18 column; 45% CH3CN—H2O (0.1% NH4OH), 1 min, to 75% at 6 min; 30 mL/min; detector set at m/z 423; retention time, 4.8 min. The eluent was concentrated using a rotary evaporator to give 8 mg of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.S(Cl)(Cl)=O.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]2[O:36][CH2:35][CH:34]([CH3:37])[N:33]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[C:32]=2[CH:43]=1.C(N(CC)CC)C>ClCCl>[CH3:41][N:40]([CH3:42])[CH2:39][CH2:38][N:33]1[C:32]2[CH:43]=[C:28]([NH:27][C:20]([C:17]3[CH:16]=[CH:15][C:14]([C:3]4[CH:4]=[CH:5][C:6]([C:8]5[N:12]=[C:11]([CH3:13])[O:10][N:9]=5)=[CH:7][C:2]=4[CH3:1])=[CH:19][CH:18]=3)=[O:21])[CH:29]=[CH:30][C:31]=2[O:36][CH2:35][CH:34]1[CH3:37]
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Reactant: CC1COc2ccc(N)cc2N1CCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc5c(c4)N(CCN(C)C)C(C)CO5)cc3)c(C)c2)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.3 %

Procedure:
2'-Methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268A1) (77 mg, 0.26 mmol) was treated with thionyl chloride (5 ml) and the mixture heated under reflux under Ar for 1 hour, then concentrated in vacuo to afford a yellow solid. This was dissolved in dichloromethane (5 ml) and treated with a solution of 6-amino-3,4-dihydro-4-(2-dimethylaminoethyl)-3-methyl-2H-1,4-benzoxazine (D14, 61.7 mg, 0.26 mmol) and triethylamine (0.11 ml, 0.78 inmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature under Ar for 24 hours, then washed with brine/saturated potassium carbonate solution (30 ml of a 1:1 solution). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to afford a brown oil. This was chromatographed on SiO2, eluting with 0-8% methanol/dichloromethane to afford the title compound as a light yellow oil (72.2 mg, 54%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:6]([OH:7])[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1.[H-].[Na+].[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1Cl>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH3:19][C:2]1([CH3:1])[CH:6]([O:7][C:23]2[N:24]=[CH:25][CH:26]=[CH:27][N:22]=2)[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1
Reactant: CCC1(COCc2ccccc2)CC(O)C(C)(C)O1
Reactant: Clc1ncccn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1(COCc2ccccc2)CC(Oc2ncccn2)C(C)(C)O1
Yield: 96.5 %

Procedure:
1 g of the alcohol of Example 3 was added to 220 mg of a 50% suspension of sodium hydride in oil dissolved in toluene (15 ml) and the mixture was stirred under reflux for 1 hour. 2-pyrimidinyl chloride (625 mg) in 10 ml toluene was added over 30 minutes. The mixture was stirred at reflux temperature for 16 hours. The mixture was then poured into brine and extracted with diethyl ether. The ether extract was dried over magnesium sulphate and evaporated to yield a residue which was purified on a silica gel column using 8% acetone in petrol as eluant to give 1.25 g (97%) of the desired product.