Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Mg]Br)(C)C.C[Si]([N:21]=[C:22]=[S:23])(C)C>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:22](=[S:23])[NH2:21])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: C[Si](C)(C)N=C=S
Agent: CC(C)[Mg]Br
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-Methyl-5,6,7,8-tetrahydroquinoline (7.3 g, 0.05 mol.) was added to a solution of isopropylmagnesium bromide [prepared from isopropylbromide (6.15 g, 0.05 mol), magnesium (1.44 g, 0.06 mol) in ether (10 ml.)] and the solution heated at 60° to remove the ether by distillation. Toluene (5 ml.) was added and the reaction mixture was heated at 120° for 2 hours, cooled, diluted with toluene (30 ml) and this solution was added to a solution of trimethylsilyl isothiocyanate (7.85 g, 0.06 mol) in toluene (50 ml.) at 0° C. The reaction mixture was stirred at room temperature for 12 hours. The solution of 3-methyl-5,6,7,8-tetrahydroquinoline-8-(N-bromomagnesio-N-trimethylsilyl)thiocarboxamide was diluted with water (15 ml.) causing hydrolysis to 3-methyl-5,6,7,8-tetrahydroquinoline-8-(N-trimethylsilyl) thiocarboxamide and subsequent hydrolysis to the title compound and the pH adjusted to 2.0 with Conc. HCl. The aqueous solution was extracted with ether and the extracts discarded. The aqueous solution was adjusted to pH 9.0 with Na2CO3 and extracted with chloroform (3 × 50 ml.). The combined extracts were washed with brine, dried and the solvent removed to give a mixture of 3-methyl-5,6,7,8-tetrahydroquinoline and the title compound (5%) which was isolated by chromatography and identified by comparison with authentic material.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:12]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1O)([CH3:15])([CH3:14])[CH3:13].[CH2:23]1[O:26][CH:24]1[CH3:25]>>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([OH:11])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3].[C:12]([CH:16]1[CH2:21][CH2:20][CH:19]([O:11][CH2:8][C:24]([CH3:23])([OH:26])[CH3:25])[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC1CO1
Reactant: CC(C)(C)C1CCCCC1O
Agent: CC(C)(C)C1CCC(O)CC1
Product: CC(C)(O)COC1CCC(C(C)(C)C)CC1

Procedure:
The synthesis was carried out in the same manner as described in Example 1, except that 20.0 g (0.128 mol) of 4-tert-butylcyclohexanol (cis:trans=4:6) and 8.8 g (0.128 mol) of 2-methylpropionoxide were used instead of 30.0 g (0.192 mol) of 2-tert-butylcyclohexanol (cis:trans=8:2) and 11.1 g (0.192 mol) of propyleneoxide. 6.2 g of 4-tert-butylcyclohexanol and 14.6 g of 1-(4-tert-butylcyclohexyloxy)-2-methyl-2-propanol (cis:trans=4:6) were obtained in a 50% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.[CH2:23]([O:25][CH:26](OCC)[O:27][CH2:28][CH3:29])[CH3:24]>>[CH2:23]([O:25][CH:26]([O:27][CH2:28][CH3:29])[N:5]1[C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]=2[C:2]([CH3:22])([CH3:1])[O:7][C:6]1=[O:8])[CH3:24]
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Reactant: CCOC(OCC)OCC
Product: CCOC(OCC)N1C(=O)OC(C)(C)c2cc(-c3cc(F)cc(C#N)c3)ccc21
Temperature: 160 °C
Yield: 33 %

Procedure:
A mixture of 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6yl)-5-fluoro-benzonitrile (0.25 g, 0.84 mmol) and triethylorthoformate (50 mL) was heated at 160° C. for 12 hours. The excess triethylorthoformate was removed in vacuo and purification via chromatography (silica gel, 20% ethyl acetate/hexane) gave 3-(1-diethoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrile (0.116 g, 33%) as a white solid: mp 123-124° C.; 1H-NMR (DMSO-d6) δ7.97 (d, 1H, J=8.68 Hz), 7.66 (bs, 1H), 7.53-7.44 (m, 2H), 7.35-7.32 (m, 2H), 6.65 (s, 1H), 3.88-3.78 (m, 2H), 3.73-3.61 (m, 2H), 1.77 (s, 6H), 1.27 (t, 6H, J=7.05 Hz); MS (ESI) m/z 295 ([M−H]−, 100%, lower MW ion consistent with loss of diethyl acetal); Anal. Calc. For C22H23FN2O4: C, 66.32, H, 5.82, N, 7.03. Found: C, 65.89, H, 5.92, N, 6.66.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[Br:13]N1C(=O)CCC1=O.CCCCCC.C(OCC)(=O)C>C(#N)C>[Br:13][C:6]1[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=[C:3]([O:2][CH3:1])[C:4]=1[NH2:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc([N+](=O)[O-])ccc1N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])cc(Br)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A clear yellow solution of 2-methoxy-4-nitroaniline (10 g, 15 59.5 mmol) in acetonitrile (300 mL) at room temperature was treated with N-bromosuccinimide (10.58 g, 59.5 mmol). The reaction was protected from light and stirred for 2 hours at room temperature. TLC (3:1 hexane:ethyl acetate) analysis showed starting material (Rf 0.14) replaced with a higher spot (Rf 0.23). The reaction was concentrated in vacuo, treated with carbon tetrachloride, filtered through celite and concentrated in vacuo to give 2-bromo-6-methoxy-4-nitroaniline as a yellow brown solid. 1H NMR (δ, CDCl3): 8.11 (1H, d, J=2.2 Hz), 7.63 (1H, d, J=2.2 Hz), 4.96 (2H, br s), 3.96 (3H, s); MS (m/z) 249, 247.
Reaction SMILES: [CH:1]([C@H:4]([NH2:7])[CH2:5]O)([CH3:3])[CH3:2].O=S(Cl)Cl.[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]=[S:24]>>[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]1[NH:7][C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][S:24]1
Reactant: CC(C)[C@H](N)CO
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](C(C)C)CS1

Procedure:
(1S)-1-Isopropyl-2-hydroxyethylamine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isopropyl-1,3-thiazolidine. The thiazolidine was reacted with cyclopentyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-isopropyl-3-cyclopentyl-1,3-thiazolidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:23][CH2:24][CH2:25]Br>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:25][CH2:24][Br:23])=[CH:11][C:10]=1[F:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCBr
Reactant: Oc1ccc(OCc2ccccc2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc(OCCBr)ccc1OCc1ccccc1

Procedure:
2-(4-Benzyloxy-3-fluorophenoxy)ethyl bromide was prepared from 4-benzyloxy-3-fluorophenol (5.45 g, 0.025 mol), potassium carbonate (8.63 g, 0.625 mol) and 25 mL of 1,2-dibromoethane as a pale yellow solid (6.6 g, 81%): mp 63-65° C. 1H NMR (CDCl3) 3.606 (t, J=6.3 Hz, 2 H), 4.218 (t, J=6.3 Hz, 2 H), 5.082 (s, 2 H), 6.582 (m, 1 H), 6.699 (m, 1 H), 6.914 (m, 1 H), 7.318-7.440 (m, 5 H).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][C:6]1[NH:7][C:8](=[O:19])[CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH:14]([CH3:18])[CH2:13]2)[N:11]=1)C>CS(C)=O>[CH3:18][CH:14]1[O:15][CH2:16][CH2:17][N:12]([C:10]2[N:11]=[C:6]([CH2:5][C:4]([OH:20])=[O:3])[NH:7][C:8](=[O:19])[CH:9]=2)[CH2:13]1
Reactant: CCOC(=O)Cc1nc(N2CCOC(C)C2)cc(=O)[nH]1
Solvent: CS(C)=O
Product: CC1CN(c2cc(=O)[nH]c(CC(=O)O)n2)CCO1

Procedure:
A first enantiomer (1.1 g), [4-(2-methylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid ethyl ester −12°, c=2.047 mg/0.5 ml DMSO, 589 nm, the characteristics of which are:
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11]Br>CCCCCC.Br.C(OCC)(=O)C>[Br:11][C:4]1[CH:5]=[CH:6][C:1]([CH:7]([CH3:10])[CH2:8][NH2:9])=[CH:2][CH:3]=1
Reactant: CC(CN)c1ccccc1
Reactant: BrBr
Agent: Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(CN)c1ccc(Br)cc1
Yield: 23 %

Procedure:
2-Phenyl-propylamine (1 g, 7.4 mmol) was dissolved in n-hexane (30 mL) and HBr/aq (5 drops) together with ZnBr on silica (1.75 mmol/g, 1 g). Br2 (14.8 mmol, 900 μL) was slowly added and the slurry was stirred over night. The slurry was diluted with ethyl acetate (300 mL) and washed with 2M Na2CO3 (300 mL). The organic phase was dried over Na2SO4, filtered and evaporated to dryness. Purification and separation of regioisomers was done on semi prep-HPLC C18-column (H2O:CH3CN, 1% NH4OAc buffer, gradient 10% to 60% CH3CN, 30 min). Yield 23%
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[N:8][CH:9]=1>O1CCCC1.O.[Na]>[Br:3][C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:8][CH:9]=1
Reactant: COC(=O)CCC(=O)Nc1cnc(Br)cn1
Agent: [Li+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)Nc1cnc(Br)cn1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
Lithium hydroxide (0.058 g, 1.0 eq.) was added at room temperature to a solution of methyl 4-[(5-bromopyrazin-2-yl)amino]-4-oxo-butanoate (Example II, 0.400 g, 1.0 eq.) in a mixture of tetrahydrofuran (15 mL) and water (5 mL). The reaction mixture was stirred at room temperature. The residue was diluted with a saturated solution of sodium hydrogenocarbonate and washed with ethyl acetate. The aqueous phase was acidified by addition of aqueous hydrochloric acid (concentrated) and extracted twice with ethyl acetate. The combined organic layer was dried on magnesium sulfate and concentrated under vacuum to give the desired compound 4-[(5-bromopyrazin-2-yl)amino]-4-oxo-butanoic acid A3 (0.343 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ 12.18 (bs, 1H), 11.02 (s, 1H), 9.12 (s, 1H), 8.60 (s, 1H), 2.67 (t, 2H), 2.55 (m, 2H) ppm. LC-MS (Method A): RT 1.08, 274 (M−H+)
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([C:19]1([CH2:22][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH2:21][O:20]1)([CH3:18])[CH3:17].O>C(O)CC>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([CH3:18])([CH3:17])[C:19]([CH2:22][N:23]1[CH:27]=[N:26][CH:25]=[N:24]1)([OH:20])[CH2:21][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(Cc1ccc(Cl)cc1Cl)C1(Cn2cncn2)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: O
Solvent: CCCO
Product: CC(C)(Cc1ccc(Cl)cc1Cl)C(O)(Cn1cncn1)Cn1cncn1
Yield: 18.8 %

Procedure:
3.7 g (52.6 mmol) of 1,2,4-triazole are added, with stirring, to a solution of 0.11 g (47 mmol) of sodium in 30 ml of n-propanol at room temperature. The mixture is heated to reflux temperature and a solution of 15.4 g (47 mmol) of 2-(2,4-dichlorophenyl-tert.-butyl)-2-(1,2,4-triazol-1-ylmethyl)oxirane in 20 ml of n-propanol is added. The reaction mixture is heated under reflux for 15 hours, then cooled and added to water. The mixture is extracted with methylenechloride, and the organic phase is dried over sodium sulphate and evaporated. The residue is purified by column chromatography (silica gel; ethyl acetate:cyclohexane=3:1). 3.5 g (18.8% of theory) of 4-(2,4-dichlorophenyl)-3,3-dimethyl-2-(1,2,4-triazol-1-ylmethyl)-1-(1,2,4-triazol-1-yl)-2-butanol of melting point 126° C. are obtained.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][S:5][C:6]([F:9])([F:8])[F:7].[OH:10][C:11]1[N:16]=[C:15]([O:17][C:18]2[N:22]([CH3:23])[N:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH:14]=[C:13]([CH3:28])[CH:12]=1.[H-].[Na+].CN1CCCC1=O>CCCCC.C(OCC)(=O)C.CN(C=O)C>[CH3:23][N:22]1[C:18]([O:17][C:15]2[CH:14]=[C:13]([CH3:28])[CH:12]=[C:11]([O:10][CH2:2][CH:3]=[CH:4][S:5][C:6]([F:9])([F:8])[F:7])[N:16]=2)=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[N:21]1
Reactant: Cc1cc(O)nc(Oc2cc(C(F)(F)F)nn2C)c1
Reactant: FC(F)(F)SC=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(OCC=CSC(F)(F)F)nc(Oc2cc(C(F)(F)F)nn2C)c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 18.4 %

Procedure:
1-Bromo-3-(trifluoromethylthio)-prop-2-ene (1.05 g, Example B) is added to a mixture of 1A (1.08 g), sodium hydride (60% in oil, 0.18 g) and N-methylpyrrolidone (20 ml) and DMF (1 ml). The reaction mixture is stirred for 6 hours at 120° C. The remaining sodium hydride is deactivated and the resulting mixture is diluted with pentane/ethyl acetate (by volume ration 1/1) and filtered through a bed of silica gel. The filtrate is washed with water. The organic layer is dried with anhydrous magnesium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (silica gel: pentane/ethyl acetate 10/1 v/v) yields 0.3 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:48]=[CH:47][C:19]([C:20]([NH:22][C@@H:23]([C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([Br:46])[CH:40]=3)[CH2:24][N:25]([CH3:38])S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)=[O:21])=[C:18]([F:49])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.SC1C=CC(C(O)=O)=CC=1.O[Li].O>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:16]2[CH:48]=[CH:47][C:19]([C:20]([NH:22][C@@H:23]([C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([Br:46])[CH:40]=3)[CH2:24][NH:25][CH3:38])=[O:21])=[C:18]([F:49])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CN(C[C@@H](NC(=O)c1ccc(-c2nc([C@H]3CC[C@H](O)[C@@H](F)C3)cnc2N)cc1F)c1cc(F)cc(Br)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C(O)c1ccc(S)cc1
Agent: [Li]O
Solvent: O
Solvent: CN(C)C=O
Product: CNC[C@@H](NC(=O)c1ccc(-c2nc([C@H]3CC[C@H](O)[C@@H](F)C3)cnc2N)cc1F)c1cc(F)cc(Br)c1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)-pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(N-methyl-2-nitrophenyl-sulfonamido)ethyl)-2-fluorobenzamide (500 g crude product from previous step) in DMF (2.0 kg) was added 4-mercaptobenzoic acid (161.5 g, 1047.7 mmol). The reaction mixture became a solution after 5 minutes and then was cooled to 10° C. After addition of LiOH.H2O (137.3 g, 3274.0 mmol) in one portion, the mixture was stirred at 25° C. for 3 hours before the temperature was cooled to 10° C. The reaction mixture was diluted with water (3.0 kg) and extracted with IPAC (3*2.5 kg). The IPAC layers was first washed with 15% aqueous Na2CO3 (2*3.0 kg) followed by water (2*3.0 kg), and then concentrated under vacuum (<100 mbar) at 40-45° C. To the resulting residue was added MeCN (1.8 kg) to give a clear solution, which was heated to 50° C. and stirred for 30 minutes. The mixture was further cooled to 10° C. in 2 hours and stirred at this temperature for a further 1 hour. After filtration of the resulting suspension, the solid cake was washed with pre-cooled MeCN (400 g, 5° C.). The wet cake was dried under vacuum (<100 mbar) at 80° C. for 18 hours to give 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide as a crystalline solid (245 g, overall yield for 2 steps is 66%, HPLC purity=98.3%, chiral purity=99.0%). Mp 115-117° C. ESI-MS (m/z): 578.1381, 580.1381 ([M+H]+, 100). HPLC (method A), retention time=7.24 min. 1H NMR (400 MHz, DMSO-D6): 8.82 (d, J=8 Hz, 1H), 8.0 (s, 1H), 8.82 (t, J=8 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.67 (d, J=8 Hz, 1H), 7.53 (s, 1H), 7.48 (d, J=8 Hz, 1H), 7.34 (d, J=8 Hz, 1H), 6.21 (br. s, 2H), 5.18 (m, 2H), 4.46-4.52, 4.32-4.37 (m, 1H), 3.52-3.60 (m, 1H), 2.80-2.94 (m, 3H), 2.36 (s, 3H), 2.23-2.25 (m, 1H), 1.95-1.98 (m, 1H), 1.76-1.86 (m, 3H), 1.51-1.62 (m, 1H), 1.39-1.48 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNS(C)(=O)=O)C1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (150 mg) in THF (2 mL) were added triethylamine (60.7 mg) and methanesulfonyl chloride (68.7 mg) under ice-cooling, and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure, distilled water was added to the residue, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (161 mg).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH:8]2[CH:13]3[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:5][CH:4]=1)#[CH:2].FC(F)(F)C([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1I)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O>[N:10]12[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11]1)[CH:8]([O:7][C:6]1[CH:16]=[CH:17][C:3]([C:1]3[NH:22][C:23]4[C:28]([CH:2]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:4][CH:5]=1)[CH2:9]2
Reactant: C#Cc1ccc(OC2CN3CCC2CC3)cc1
Reactant: O=C(Nc1ccccc1I)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1ccc2[nH]c(-c3ccc(OC4CN5CCC4CC5)cc3)cc2c1

Procedure:
Under N2, the mixture of product from Example 6A (114 mg, 0.5 mmol), the product from Example 6B (157 mg, 0.5 mmol), Cul (Strem Chemicals, 14 mg, 0.075 mmol), PPh3 (Aldrich, 39 mg, 0.15 mmol) and K3PO4 (212 mg, 1 mmol) in dioxane (5 mL) was stirred at 80° C. for 20 h. After the reaction was complete, it was diluted with EtOAc (30 mL) and washed with brine (2×5 mL). The organic solution was concentrated under reduced pressure and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3 H2O, 90:10:1, Rf. 0.30) as solid (70 mg, yield, 44%). 1H NMR (300 MHz, CD3OD) δ 1.45-1.59 (m, 1H), 1.65-1.91 (m, 2H), 2.00-2.14 (m, 1H), 2.17-2.24 (m, 1H), 2.75-3.01 (m, 5H), 3.31-3.42 (m, 1H), 4.54-4.62 (m, 1H), 6.66 (d, J=0.7 Hz, 1H), 6.93-7.00 (m, 3H), 7.01-7.08 (m, 1H), 7.35 (dq, J=8.2, 1.0 Hz, 1H), 7.48 (dq, J=7.8, 0.7 Hz, 1H), 7.71 (dt, J=8.8, 2.6 Hz, 2H) ppm. MS (DCI/NH3): m/z 319 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([CH3:37])[CH:29]=1>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:30]([CH3:37])[CH:29]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: COc1ccc(B(O)O)c(C)c1
Product: COc1ccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(C)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 4-methoxy-2-methylphenylboronic acid (CAS RN 208399-66-0). Pale yellow sticky solid (67%). MS (ESI): m/z=469.2 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]2[CH2:14][C@@H:9]1[CH2:10][N:11]2[C:15]([C:17]1[CH:18]=[N:19][C:20]([NH:23][C:24]2[N:25]=[CH:26][C:27]3[CH:32]=[C:31]([C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[N:30]([CH:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[C:28]=3[N:29]=2)=[CH:21][CH:22]=1)=[O:16])=O)(C)(C)C.CN(C)C(C1NC2N=CN=CC=2C=1)=O>>[CH3:35][N:34]([CH3:36])[C:33]([C:31]1[N:30]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:28]2[N:29]=[C:24]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([C:15]([N:11]4[CH2:10][C@H:9]5[CH2:14][C@@H:12]4[CH2:13][NH:8]5)=[O:16])=[CH:18][N:19]=3)[N:25]=[CH:26][C:27]=2[CH:32]=1)=[O:37]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@H]5C[C@@H]4CN5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Agent: CN(C)C(=O)c1cc2cncnc2[nH]1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@H]5C[C@@H]4CN5)cn3)nc2n1C1CCCC1
Yield: 22 %

Procedure:
Following deprotection method 2, 5-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-(R,R)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester was converted to 7-Cyclopentyl-2-[5-(R,R)-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (20 mg) in 22% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.65-1.85 (m, 4H) 2.03 (s, 2H) 2.06-2.19 (m, 6H) 2.59 (br. s., 2H) 3.18 (s, 7H) 3.33 (d, J=9.60 Hz, 1H) 3.52 (br. s., 1H) 3.78 (br. s., 2H) 4.72-4.94 (m, 1H) 6.38-6.54 (m, 1H) 7.96 (d, J=9.09 Hz, 1H) 8.56 (s, 1H) 8.61 (d, J=8.59 Hz, 1H) 8.84 (br. s., 1H); HRMS m/z, (M+H)+: 475.2582.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:22]3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:25]4[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=4[N:23]=3)[CH2:19][CH2:20]O)=[CH:14][CH:13]=2)=[N:4]1)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:65])C(=O)C1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:65][CH2:20][CH2:19][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([C:5]2[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:11]3[N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:17][CH:16]=1)[C:22]1[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[C:25]2[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=2[N:23]=1
Reactant: CCn1nc(-c2ccc(C(CCO)c3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccc(C(CCBr)c3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of 3-{4-(1-ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl}-3-(1-[(2-(trimethylsilyl)ethoxy)methyl]-1H-benzo[d]imidazol-2-yl)propan-1-ol (80 mg) and PPh3 (43.7 mg) in DMF (2 mL) was added NBS (27.0 mg) at room temperature. The mixture was stirred at room temperature under a dry atmosphere for 1 h. The mixture was neutralized with saturated NaHCO3 aqueous solution at 0° C. and extracted with AcOEt. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give the title compound (75 mg).