Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1([CH2:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=3[S:22](=[O:36])(=[O:35])[N:21]=2)[C:10]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44](OC(=O)C)(=[O:46])[CH3:45].C(N(CC)CC)C>ClC(Cl)C>[CH2:1]([N:8]([C:9]1([CH2:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=3[S:22](=[O:36])(=[O:35])[N:21]=2)[C:10]1=[O:37])[C:44](=[O:46])[CH3:45])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)CCC1(NCc2ccccc2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(=O)N(Cc1ccccc1)C1(CCC(C)(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 75 °C
Yield: 23.5 %

Procedure:
To a solution of the product of Example 74G (20 mg, 0.032 mmol) in dichloroethane (0.5 mL), acetic anhydride (5 μL, 0.048 mmol) and triethylamine (13 μL, 0.096 mmol) were added. The reaction solution was heated at 75° C. for 96 h. After cooling to room temperature, the solution was concentrated in vacuo. The resulting residue was dissolved in methanol (0.5 mL) and treated with excess of K2CO3 for 30 min. The mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was taken up in ethyl acetate (1 mL), washed with aqueous 1 N HCl, dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (1%→2%→3% methanol/dichloromethane) afforded the title compound as a brown solid (5 mg, 24%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.25-0.42 (m, 1H), 0.47 (s, 9H), 0.73-0.96 (m, 1H), 1.68-2.05 (m, 5H), 3.02 (s, 3H), 5.06 (d, J=18.02 Hz, 1H), 5.24-5.42 (m, 1H), 7.27-7.61 (m, 10H), 7.83 (d, J=6.99 Hz, 1H), 10.01 (s, 1H); MS m/z 665.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[C:22]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:30][C:29]2[CH:31]=[CH:32][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(C(C)(C)C)cc1)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1

Procedure:
Monoimine (1, 2.8 g, 10 mmol) and 4-tert-butylaniline (1.49 g, 10 mmol) were dissolved in 100 ml of toluene. To this solution, 4 Å molecular sieves and a small amount of p-toluenesulphonic acid (0.1 mmol) were added. After standing for 5 days with addition of more 4 Å molecular sieves, the mixture was refluxed for 2 hours. After filtration the solvent was removed in vacuo. The residue was washed with methanol and recrystallised from ethanol. Yield 2.4 g (58%) of mixed diimine (2). 1H-NMR (CDCl3) δ 8.42 (d, 1H, Py-Hm), 8.34 (d, 1H, Py-Hm), 7.86 (t, 1H, Py-Hp), 7.38 (d, 2H, ArH), 6.89 (s, 2H, ArH), 6.78 (d, 2H, ArH), 2.42 (s, 3H, Me), 2.29 (s,3H, Me), 2.22 (s, 3H, Me), 2.00 (s, 6H, Me), 1.34 (s, 9H, But).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[F:24])[O:17][CH2:18][CH2:19][Br:20].ClC1C=CC(OCCBr)=CC=1F.FC1C=C(O)C=CC=1F.BrCCBr>>[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[F:24])[O:17][CH2:18][CH2:19][S:12][C:10]1[N:11]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[F:24])[O:17][CH2:18][CH2:19][Br:20]
Reactant: Cc1cc(C)n2nc(S)nc2n1
Agent: Fc1cc(OCCBr)ccc1Cl
Agent: Fc1ccc(OCCBr)cc1F
Agent: Oc1ccc(F)c(F)c1
Solvent: BrCCBr
Product: Cc1cc(C)n2nc(SCCOc3ccc(F)c(F)c3)nc2n1
Yield: 36 %

Procedure:
The title compound was prepared according to the experimentals described for Example 1 above from 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol and 3,4-difluorophenoxy-ethylbromide in 36% yield. The reagent 3,4-difluorophenoxy-ethylbromide was prepared by a similar procedure for the synthesis of 4-chloro-3-fluorophenoxy-ethylbromide in Example 4 above from 3,4-difluorophenol and 1,2-dibromoethane. EM (calc.): 336.1; MS (ESI) m/e: 337.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:16][C:17]([C:19]1[O:20][C:21]2[C:27](Br)=[CH:26][CH:25]=[CH:24][C:22]=2[CH:23]=1)=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1[O:20][C:21]2[C:27]([N:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)=[CH:26][CH:25]=[CH:24][C:22]=2[CH:23]=1)=[O:18])[CH3:15]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCOC(=O)c1cc2cccc(Br)c2o1
Product: CCOC(=O)c1cc2cccc(N3CCN(Cc4ccccc4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1a starting from benzylpiperazine (16.1 mL, 92.6 mmol) and 7-bromo-benzofuran-2-carboxylic acid ethyl ester (16.6 g, 61.7 mmol). The product was purified by flash chromatography (SiO2; hexane/EtOAc, gradient 0-50%). Yield: 14 g (63%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([N:18]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:17])=[CH:12][CH:11]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.O.NN>O1CCOCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([NH2:18])[CH3:17])=[CH:12][CH:11]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1-c1ccc(C(C)N2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(F)cc1-c1ccc(C(C)N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
The organic phase was washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue chromatographed on silica gel to give to give 2-{1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-isoindole-1,3-dione (0.31 g, 0.82 mmol, 41%). To a solution of 2-{1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-isoindole-1,3-dione (0.31 g, 0.8 mmol) in dioxan/methanol (1:1, 10 ml) was added hydrazine hydrate (0.83 g, 46.5 mmol). The reaction was stirred at room temperature for 24 h. The solvent was evaporated and dichloromethane added. The resultant white solid was filtered off and dried to give 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethylamine (0.21 g, 0.8 mmol, 100%) as a clear oil. To a solution of 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethylamine (0.1 g, 0.4 mmol) in dichloromethane (2 ml) was added triethylamine (123 mg, 1.2 mmol) and 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonylchloride (111 mg, 0.45 mmol). The reaction mixture was agitated for 16 h and quenched with saturated aqueuos sodium bicarbonate solution. The organic phase was washed with water, brine and dried over anhydrous magneium sulfate. The residue was chromatographed on silica gel to give the title compound (42 mg, 0.1 mmol, 25%). 1H NMR (400 MHz, CDCl3): δ 8.00 (d, 1H), 7.45 (m, 3H), 7.35 (dd, 1H), 7.21 (d, 2H), 4.86 (d, 1H), 4.60 (q, 1H), 3.96 (s, 3H), 3.75 (s, 3H), 1.50 (b, 3H) ppm; MS (ESI) m/z: 459.3 [M+H]+.
Reaction SMILES: CC1NC([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])=C(C)N=1.I[C:20]1[NH:24][C:23]([C:25]2([CH3:29])[CH2:28][O:27][CH2:26]2)=[N:22][C:21]=1[C:30]#[N:31].IC1NC(C)=NC=1C>>[C:30]([C:21]1[N:22]=[C:23]([C:25]2([CH3:29])[CH2:28][O:27][CH2:26]2)[NH:24][C:20]=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([O:13][CH3:14])=[O:12])#[N:31]
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Reactant: CC1(c2nc(C#N)c(I)[nH]2)COC1
Agent: Cc1nc(C)c(I)[nH]1
Product: COC(=O)c1ccc(C)c(-c2[nH]c(C3(C)COC3)nc2C#N)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.6, except 5-iodo-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile (compound 202.3) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 312 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH2:9][OH:10])[C:3]=1[OH:11].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>ClCCl>[F:1][C:2]1[C:3]([OH:11])=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH:9]=[O:10]
Reactant: OCc1ccc(F)c(F)c1O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: O=Cc1ccc(F)c(F)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a stirred solution of 2,3-difluoro-6-(hydroxylmethyl)phenol (2.5 g, 15.62 mmol) in dichloromethane (20 mL) was added a suspension of DDQ (5.32 g, 23.43 mmol) in dichloromethane (10 mL) at −5-0° C. The reaction mixture was stirred at room temperature overnight. TLC indicated absence of starting material. Reaction mixture was filtered through a bed of celite and the filtrate was concentrated in vacuum. The crude compound was purified by column chromatography over silica gel using dichloromethane (100%) as eluent to give the aldehyde derivative (2 g, 83% yield) MS: m/z 157 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O.CCN(C(C)C)C(C)C.[NH2:23][CH2:24][CH:25]([OH:37])[CH2:26][N:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[CH2:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:35][CH2:36][N:27]1[CH2:26][CH:25]([OH:37])[CH2:24][NH:23][C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(OCC(=O)O)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a stirred mixture of 2-(3-methoxyphenoxy)acetic acid (100 mg, 0.549 mmol) in DCM (5 mL) was added DIEA (106 mg, 0.824 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (113 mg, 0.549 mmol) and Bop-Cl (168 mg, 0.66 mmol). The mixture was stirred at 25° C. for 16 hours then the reaction mixture was quenched with water (20 mL), extracted with DCM (3×20 mL). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the desired product (61 mg, Yield 32%). 1H NMR (400 MHz, MeOD) δ 7.21 (dd, J1=J2=8.0 Hz, 1H), 7.17-7.03 (m, 4H), 6.59-6.51 (m, 3H), 4.52 (s, 2H), 4.05-4.01 (m, 1H), 3.77 (s, 3H), 3.73 (d, J=2.8 Hz, 2H), 3.47-3.37 (m, 2H), 2.92 (d, J=5.2 Hz, 2H), 2.87 (d, J=5.2 Hz, 2H), 2.61 (d, J=6.0 Hz, 2H). LCMS (m/z): 371.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[C:14]([F:44])=[C:15]([C:19]2[N:20]=[C:21]([CH:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)[S:22][C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[N:25]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:10].C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:20]=[C:21]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:22][C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[N:25]=2)[C:14]=1[F:44])(=[O:10])=[O:11]
Reactant: Cc1nccc(-c2sc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nccc(-c2sc(C3CCNCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (60 mg, 0.093 mmol) in dichloromethane (DCM) (2 mL) was added TFA (0.5 μL, 6.49 μmol), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was purified using RP-HPLC. The TFA salt was neutralized to give 32 mg of title compound. MS (ESI): 546.1 [M+1]+.
Reaction SMILES: [C:1]([C@@H:3]([NH:23][C:24]([C:26]1([NH:32]C(=O)OC(C)(C)C)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)#[N:2]>C(O)=O>[NH2:32][C:26]1([C:24]([NH:23][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)=[O:25])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2ccc(C[C@@H](C#N)NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)cc2)cc1
Solvent: O=CO
Product: CC(C)S(=O)(=O)c1ccc(-c2ccc(C[C@@H](C#N)NC(=O)C3(N)CCOCC3)cc2)cc1
Temperature: 50 °C
Yield: 27.2 %

Procedure:
To (S)-tert-butyl 4-(1-cyano-2-(4′-(isopropylsulfonyl)biphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 4, step (ii(ii)), 300 mg) was added formic acid (4 mL) and the mixture heated to 50° C. for 20 min. The mixture was evaporated to dryness, dissolved in methanol (10 mL), re-evaporated to dryness, dissolved in methanol (6 mL) and purified on reverse phase HPLC eluting with 25 to 95% methanol in 0.1% aqueous TFA on a Waters SunFire column. The material was converted to free base by evaporating the relevant fractions, dissolving in dichloromethane (20 mL) and shaking with saturated sodium bicarbonate solution (20 mL). The dichloromethane was dried and evaporated to afford the titled compound (67 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[C:15]2[CH2:16][N:17]([S:20]([C:23]3[CH:30]=[CH:29][C:26]([CH2:27][OH:28])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:18][CH2:19][C:14]=2[CH:13]=[CH:12]1.C(N(CC)CC)C>ClCCl.C(OCC)C>[O:11]1[C:15]2[CH2:16][N:17]([S:20]([C:23]3[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:18][CH2:19][C:14]=2[CH:13]=[CH:12]1
Reactant: O=S(=O)(c1ccc(CO)cc1)N1CCc2ccoc2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1ccc(S(=O)(=O)N2CCc3ccoc3C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1.07 g (8.44 mmol) of oxalyl chloride in 50 ml of dichloromethane, 1.20 ml (16.9 mmol) of dimethyl sulfoxide was added dropwise at -78° C., followed by stirring for 5 minutes. To this solution, a solution of 1.650 g of the above crude 4-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-ylsulfonyl)benzyl alcohol in 10 ml of dichloromethane was added at -78° C., followed by stirring for 15 minutes. To this mixture, 4.70 ml (33.7 mmol) of triethylamine was added; the mixture was allowed to warm to room temperature. The reaction mixture was diluted with diethyl ether, washed with water and dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane) and crystallized from diethyl ether-hexane to yield the desired product.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:26])[CH:13]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[CH:19]2)[CH3:14])[CH3:10].[CH2:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC(O)=O>C1COCC1.CCOCC>[CH2:9]([O:11][C:12](=[O:26])[C:13]([CH3:14])([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[CH:19]2)[CH:39]([C:38]1[CH:37]=[CH:36][C:35]([O:34][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:42][CH:41]=1)[OH:40])[CH3:10]
Reactant: CCOC(=O)C(C)Oc1ccc2ncccc2c1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(Oc1ccc2ncccc2c1)C(O)c1ccc(OCc2ccccc2)cc1
Reaction time: 0.05 h
Yield: 86 %

Procedure:
To a LDA solution (42 mL, 1.5 M solution in THF) in 65 mL of dry THF at −78° C., a solution of 2-(quinolin-6-yloxy)-propionic acid ethyl ester (8.61 g, 0.035 mol) in 65 mL of dry THF was cannulated in. The resulting solution is allowed to stand at −78° C. for 3 min. Solid 4-benzyloxybenzaldehyde (6.71 g, 0.032 mol) was added and resulting mixture was allowed to stand at −78° C. for 5 min until all solid dissovled in the solution. Reaction was then quenched with AcOH (6.03 mL, 0.105 mol) in 60 mL of THF at −78° C. The mixture was then diluted with Et2O and washed with sat'NH4Cl, water and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography to give 3-(4-benzyloxy-phenyl)-3-hydroxy-2-methyl-2-(quinolin-6-yloxy)-propionic acid ethyl ester in 86% yield. A of solution of 2.75 g of give 3-(4-benzyloxy-phenyl)-3-hydroxy-2-methyl-2-(quinolin-6-yloxy)-propionic acid ethyl ester (6.01 mmol), trifluoroacetic acid (2.8 mL, 36.1 mmol), triethylsilane (5.8 mL, 36.1 mmol) in 80 mL of dichloroethane was heated to reflux for 50 h. The mixture was cooled to r.t. and diluted with Et2O and washed with sat′ NaHCO3, water and brine. Organic layer was dried over Mg SO4, filtered and concentrated. Residue was purified by chromatography (5% MeOH in CH2Cl2) to give 86% of title compound as light yellow oil. 1H NMR (400 MHz, CDCl3) δδ 8.78 (dd, 1H, J=4.4, 1.6 Hz), 8.00 (d, 1H, J=9.2 Hz), 7.98 (d, 1H, J=8.8 Hz), 7.45-7.32 (m, 7H), 7.19 (d, 2H, J=8.8 Hz), 7.04 (d, 1H, J=3.2 Hz), 6.93 (d, 2H, J=8.8 Hz), 5.06 (s, 2H), 4.23 (q, 2H, J=7.1 Hz), 3.38, 3.18 (ABq, 2H, J=13.8 Hz), 1.53 (s, 3H), 1.19 (t, 3H, J=7.1 Hz). MS (ES+) m/z mass calcd for C28H28NO4 (m+1) 442, found 442.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH:10][CH:11]1[CH2:13][CH2:12]1.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH3:26])[C:23](O)=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([O:18][C:19](=[O:20])[NH:21][C@H:22]([C:23](=[O:24])[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[C:3]=1[NH:10][CH:11]1[CH2:13][CH2:12]1)[CH3:26])([CH3:15])([CH3:16])[CH3:17]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)c(Br)c1NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)c(Br)c1NC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A mixture of 3-bromo-N2-cyclopropyl-4-fluorobenzene-1,2-diamine (759 mg, 3.10 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (644 mg, 3.41 mmol), HOAt (464 mg, 3.41 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (654 mg, 3.41 mmol) in DCM (20 mL) was stirred at 0° C. for 1 h. The reaction mixture was then partitioned between DCM and a saturated solution of NaHCO3. The organic fraction was dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the title compound (1.05 g, 81%) as a pale beige solid. LCMS (Method C): RT 3.66 min [M+H]+ 416.05
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]#[C:24][Si](C)(C)C)=[N:21][CH:22]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:2]2[CH:3]=[C:4]([C:8]3([CH3:15])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]3)[CH:5]=[CH:6][CH:7]=2)=[N:21][CH:22]=1
Reactant: C[Si](C)(C)C#Cc1ccc(Cl)cn1
Reactant: CC1(c2cccc(I)c2)COCC(N)=N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(c2cccc(C#Cc3ccc(Cl)cn3)c2)COCC(N)=N1

Procedure:
In a manner analogous to that described in Example 42, the reaction of (RS)-5-(3-iodo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (intermediate XII-2) with 5-chloro-2-trimethylsilanylethynyl-pyridine (EP385210) was performed. In addition, after combination of solution 1 and 2, a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 0.47 ml) was added. The 5-[3-(5-chloro-pyridin-2-ylethynyl)-phenyl]-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine was obtained as a white foam. MS (ISP): m/z=326.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9][C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][C:6]=2[CH:23]=1.B([O-])([O-])OC1C=CC(OCC)=C(OCC)C=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[N:11]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:23][C:6]=2[CH2:7][C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:9][CH:10]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCOc1ccc(OB([O-])[O-])cc1OCC
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)C1=CC=Nc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 247 %

Procedure:
A mixture of methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.0 g), 3,4-diethoxyphenyl borate (0.63 g), 1M potassium carbonate solution (8 ml), ethanol (8 ml) and toluene (50 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.12 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-benzazepine-4-carboxylate (1.3 g) as colorless crystals.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:32].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:32])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31])[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2F)C(=O)O1
Reactant: [OH-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(F)cc1F)C(=O)O

Procedure:
In analogy with Example 1i), 3.1 g (7.18 mmol) 5(S)-[1(S)-(Boc-amino)-2-phenyl-ethyl]-3(R)-[(2,4-difluorophenyl)methyl]dihydrofuran-2-(3H)-one in 77 ml of dimethoxyethane and 19 ml of water are hydrolysed with 28.7 ml of a 1M lithium hydroxide solution (19 h at RT) to give the title compound: tRet (II)=14.7 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[C:23]([N+:25]([O-])=O)[CH:24]=[C:19]4[CH:18]=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:29][CH3:30]>C(O)(=O)C.CCOC(C)=O.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:28])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[C:23]([NH2:25])[CH:24]=[C:19]4[CH:18]=[N:17]3)[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:29][CH3:30]
Reactant: COc1cc(N2CCN(C(=O)Cn3ncc4cc([N+](=O)[O-])cnc43)CC2)ccc1Cl
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(N2CCN(C(=O)Cn3ncc4cc(N)cnc43)CC2)ccc1Cl
Temperature: 25 °C

Procedure:
1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(5-nitro-pyrazolo[3,4-b]pyridine-1-yl]-ethanone (15 Mg) is combined with 200 Mg of iron powder in 2 mL of acetic acid at 100° C. for 30 min. After cooling to rt, the reaction solution was diluted with EtOAc and filtered. The filtrate was evaporated in vacuo and purified by HPLC to provide 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(5-amino-pyrazolo[3,4-b]pyridine-1-yl]-ethanone: HPLC retention time=1.46 minutes (Agilent Zorbax SB-C18, 2.1×50 Mm, 5μ, 35° C.) using 1 mL/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expect=414.2, found=415.1.