Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH2:34][OH:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.I[C:38]1[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=1>C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]([CH3:36])([CH2:34][OH:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:38]3[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cn1ccc(I)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(O)CO)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(O)CO)(c2ccccc2)OC1=O

Procedure:
A mixture of (S)-6-(2,3-dihydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (105 mg, 211.9 mmol), 4-iodo-1-methylpyridin-2(1H)-one (65 mg, 275.5 mmol), Pd(PPh3)2Cl2 (20 mg) in aq. Cs2CO3 solution (3 mL) was stirred at reflux for 2 h. After the reaction was finished, the mixture was washed with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative HPLC to afford two isomers of (6S)-6-(2,3-dihydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]>Cl>[OH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([OH:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(O)C(=O)Cc1ccc(O)c(O)c1
Agent: Cl
Product: O=C(O)C(O)Cc1ccc(O)c(O)c1
Yield: 40.3 %

Procedure:
Into 0.17 mol β-(3,4-dihydroxylphenyl)pyruvic acid, 112 g zinc amalgam and 1808 mL of 1.4 mol·L−1 hydrochloric acid solution were added, and the reaction was performed under heating and refluxing for 8 h. After filtration, the filtrate was extracted using ethyl acetate repeatedly, dried using anhydrous Na2SO4. After removal of ethyl acetate, β-(3,4-dihydroxylphenyl)-α-hydroxylpropionic acid was obtained in a yield of 40.3%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: Nc1ccc(C(=O)Cl)cc1
Yield: 100 %

Procedure:
Thionyl chloride (10 ml) was added to 4-aminobenzoic acid (1.0 g, 7.29 mmol) and the solution was heated to reflux for 16 hr. Thionyl chloride was removed under vacuum to yield 4-amino-benzoyl chloride (1.13 g, 100%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=[O:2].[NH+]1C=CC=CC=1.OCC[CH2:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:18][CH:17]=1>C(Cl)Cl>[CH:15]([C:16]1[CH:34]=[CH:33][C:19]([CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:18][CH:17]=1)=[O:2]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: O=S(=O)(NCCc1ccc(CCCO)cc1)c1ccc(Cl)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
Into a solution of 12.8 g. (59.4 mmole) pyridinium chlorochromate and 250 ml. methylene chloride are introduced, with stirring at ambient temperature, 14.0 g. (39.6 mmole) 4-chlorobenzenesulphonic acid-[4-(3-hydroxypropyl)-phenethylamide]. The reaction mixture is stirred for a further hour and then poured off from insolubles. The methylene chloride phase is chromatographed with a short column (silica gel/methylene chloride) and evaporated. Yield 10.8 g. (78% of theory); m.p. 65°-66° C. Oxime: m.p. 156°-158° C. (recrystallised from toluene).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.Cl[C:55]([O:57][CH3:58])=[O:56]>C(Cl)Cl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[O:26])[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:55]([O:57][CH3:58])=[O:56])[CH2:9][CH2:10]2)=[O:44])=[CH:22][CH:21]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Yield: 81.4 %

Procedure:
To a 50 mL round-bottomed flask equipped with stirring was added tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl)carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Example 20) (462 mg, 0.75 mmol) and CH2Cl2 (15 mL) followed by DIEA (0.16 mL, 0.9 mmol). The reaction mixture was stirred for 5 min at RT then treated with methyl chloroformate (Aldrich) (84.6 mg, 0.9 mmol) at 0° C. The reaction mixture was stirred at RT for 12 h then quenched with satd NaHCO3 (15 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×15 mL). The organic fractions were combined, washed with satd NaCl (15 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (412 mg). MS (ESI, pos. ion) m/z: 675 (M+1); MS (ESI, neg. ion) m/z: 673 (M−1). Calc'd for C11H13ClN4O6: 674.29.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10](COCC3C=CC=CC=3)[CH:9]=[C:8]([CH2:20][NH:21][CH2:22][C@H:23]([OH:27])[CH2:24][S:25][CH3:26])[C:4]=2[N:5]=[CH:6][N:7]=1.O.NN>N.CO.[Pd]>[NH2:1][C:2]1[C:3]2[NH:10][CH:9]=[C:8]([CH2:20][NH:21][CH2:22][C@H:23]([OH:27])[CH2:24][S:25][CH3:26])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CSC[C@@H](O)CNCc1cn(COCc2ccccc2)c2c(N)ncnc12
Agent: [Pd]
Agent: N
Agent: NN
Solvent: CO
Solvent: O
Product: CSC[C@@H](O)CNCc1c[nH]c2c(N)ncnc12
Reaction time: 0.67 h

Procedure:
The product from Example 2.5 (0.08 g, 0.206 mmol) was dissolved in 7M NH3-MeOH solution (8 ml) and Pd black (80 mg) added followed by hydrazine hydrate (1.2 ml). The mixture was stirred for 40 mins, filtered and the solvent evaporated. The residue was chromatographed on silica gel (CH2Cl2-7M NH3 in MeOH, 85:15) to give(S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-3-(methylthio)propan-2-ol (0.042 g, 76%) as a colourless solid. [α]D20 −12.4 (c, 0.355, MeOH). 1H NMR (CD3OD), δ 8.16 (s, 1H), 7.48 (s, 1H), 4.00 (d, J=13.5 Hz, 1H), 3.92-3.84 (m, 2H), 2.85 (dd, J=12.2, 3.5 Hz, 1H), 2.65 (dd, J=12.2, 8.5 Hz, 1H), 2.55 (d, J=6.5 Hz, 2H), 2.10 (s, 3H). 13C NMR (CD3OD, referenced to the centre line of CD3OD at 49.0 ppm), δ 152.1, 150.9, 146.6, 129.1, 115.4, 114.2, 70.2, 54.6, 43.5, 40.4, 16.2. +ESMS Found 268.1241 (M+H)+ C11H18N5OS requires 268.1232.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH:10](OC)[O:11]C)[NH:6][C:7]=1[CH2:8][CH3:9])[CH3:2]>S(=O)(=O)(O)O>[CH2:8]([C:7]1[N:6]=[C:5]([CH:10]=[O:11])[NH:4][C:3]=1[CH2:1][CH3:2])[CH3:9]
Reactant: CCc1nc(C(OC)OC)[nH]c1CC
Agent: O=S(=O)(O)O
Product: CCc1nc(C=O)[nH]c1CC
Yield: 28.5 %

Procedure:
The same operation as in Example (33b) was performed using 4,5-diethyl-2-(dimethoxymethyl)-1H-imidazole obtained in Example (43a) (about 8.12 mmol) and 2 N sulfuric acid (40 mL), to obtain 352 mg of the title compound as a white solid (28%).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH2:12][CH3:13].[C:18](Cl)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[CH2:12]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:5][CH2:4][C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH3:13]
Reactant: CCN1CCCCC1CCc1ccccc1N
Reactant: COc1ccc(C(=O)Cl)cc1
Product: CCN1CCCCC1CCc1ccccc1NC(=O)c1ccc(OC)cc1

Procedure:
Reaction of 2-(2-aminophenethyl)-1-ethylpiperidine with anisoyl chloride according to the procedure of Example 25 provides 2'-[2-(1-ethyl-2-piperidyl)ethyl]-p-anisanilide, m.p. 136.5°-137.5°C. (corr.), from ethyl acatate.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[C:1]([C:3]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:11][CH:10]=2)[CH2:4][CH2:5][N:6]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:7][CH2:8]1)#[N:2]
Reactant: O=C1CCCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2(C#N)CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ccc(C2(C#N)CCN(C3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.4 %

Procedure:
Compound 348 (230 mg, 0.77 mmol) was dissolved in 20 mL MeOH and 1 mL HOAc. To the solution was added cyclopentanone (280 μL, 3.08 mmol) and the mixture was stirred at RT for 2.5 hours. Then NaBH3CN (290 mg, 4.62 mmol) was added, and the mixture was stirred at RT for overnight. It was concentrated in vacuo, diluted with EtOAc 150 mL, washed with 1N NaOH and water, dried, concentrated in vacuo to dryness to give crude tert-butyl 4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenylcarbamate (349, 280 mg, 98%). It was treated with 4N HCl in dioxane at RT for 4 hours and concentrated in vacuo to dryness to give 4-(4-aminophenyl)-1-cyclopentylpiperidine-4-carbonitrile hydrochloride (350, 250 mg, quantitative yield).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:28])[N:7]([CH:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)[C:15]#[N:16])[C:8]2=[O:13])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:28])[N:7]([CH:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)[C:15]#[N:16])[C:8]2=[O:13]
Reactant: CCOc1cc(C(C#N)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(C(C#N)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Reaction time: 3 h
Yield: 120.4 %

Procedure:
A mixture of 2-(nitro-1,3-dioxoisoindolin-2-yl)-2-(3-ethoxy-4-methoxyphenyl)ethanenitrile (3.9 g, 7.8 mmol) and 10% Pd/C (0.6 g) in methanol (150 mL) was hydrogenated at 50 psi for 3 hours. The mixture was filtered through celite, and the celite was washed with methylene chloride. The filtrate was concentrated and the residue was purified by chromatography (SiO2, CH2Cl2:CH3OH 95:5) to give 3.3 g (91%) of 2-(4-amino-1,3-dioxoisoindolin-2-yl)-2-(3-ethoxy-4-methoxyphenyl)ethanenitrile; 1H NMR (DMSO-d6) δ 7.50-7.43 (dd, J=7.3 and 8.3 Hz, 1H), 7.03-6.91 (m, 5H), 6.55 (s, 2H), 5.55-5.48 (dd, J=6.6 and 9.9 Hz, 1H), 3.99 (q, J=7.0 Hz, 2H), 3.72 (s, 3H), 3.76-3.48 (m, 2H), 1.31 (t, J=7 Hz, 3H); 13C NMR (DMSO-d6) δ 168.81, 167.59, 148.88 146.82, 135.55, 131.56, 129.70, 121.86, 121.80, 119.27, 118.26, 112.10, 111.82, 111.06, 63.82, 55.48, 49.46, 20.54, 14.61.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@@H:15]([C:26]([OH:28])=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)(=[O:13])=[O:12].C(N(C(C)C)C(C)C)C.O[CH2:39][C@H:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:49]([O:48][C:46]([N:42]1[CH2:43][CH2:44][CH2:45][C@H:40]([CH2:39][O:27][C:26](=[O:28])[C@@H:15]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[NH:14][S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:13])=[O:12])[CH2:41]1)=[O:47])([CH3:52])([CH3:50])[CH3:51]
Reactant: O=C(O)[C@@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](COC(=O)[C@@H](Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccc3ccccc3c2)C1
Reaction time: 15 h
Yield: 66.7 %

Procedure:
A solution of 1.0 g of N-2-naphthylsulfonyl-(D)-tryptophan in 20 ml of DMF is treated with 0.5 ml of ethyldiisopropylamine. After the addition of 0.6 g of t-butyl (S)-3-hydroxymethyl-1-piperidinecarboxylate (Example 3c) and 1.1 g of benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate the reaction mixture is stirred for 15 hours. The solvent is evaporated and the residue is taken up in water and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried and evaporated. Chromatography over silica gel with ethyl acetate gives 1.0 g of N-(2-naphthylsulfonyl)-D-tryptophan (S)-l-t-butyoxycarbonyl-3-piperidinylmethyl ester.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]#[CH:23])[CH:18]=3)[NH:13][C:12](=[O:24])[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:25]1([CH3:36])[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[C:26]=1[CH:33]1[CH2:35][O:34]1.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCOCC1>[OH:34][CH:33]([C:26]1[C:27]([CH3:32])=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=1[CH3:36])[CH2:35][N:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[CH:16][CH:15]=2)[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)=[N:11][C:12]1=[O:24]
Reactant: Cc1cc(C)c(C2CO2)c(C)c1
Reactant: C#CCOc1ccc2[nH]c(=O)nc(-c3ccc(C(C)C)cc3)c2c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2CC(O)c1c(C)cc(C)cc1C

Procedure:
A mixture of 0.5 g (1.57 mmol) 4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one, 0.254 g (1.57 mmol) mesityl oxirane, 35.7 mg (0.157 mmol) benzyltriethylammonium chloride and 21.7 mg (0.157 mmol) potassium carbonate is stirred in 1 ml dioxane at 90° C. for 6 days. The reaction mixture is extracted with water/dichloromethane and, after evaporation of the organic phases, the residue is purified by preparative reversed phase HPLC.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[C:21](=[O:22])[NH:20][C:19]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[N:18]2)(=[O:16])=[O:15])=[C:10]([O:30][CH3:31])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][CH:40]([OH:45])[C:41]([F:44])([F:43])[F:42]>CN(C)C=O.[Cl-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[C:21](=[O:22])[N:20]([CH2:39][CH:40]([OH:45])[C:41]([F:44])([F:43])[F:42])[C:19]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)=[N:18]2)(=[O:16])=[O:15])=[C:10]([O:30][CH3:31])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)NC(C)(C)C)ccc1S(=O)(=O)n1nc(-c2ccc(Cl)cc2)[nH]c1=O
Reactant: OC(CBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC(C)(C)C)ccc1S(=O)(=O)n1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Temperature: 75 °C
Reaction time: 8 h

Procedure:
An amount of 50 mg (0.108 mmol) of N-tert-butyl-4-{[3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]sulphonyl}-3-methoxybenzenecarboxamide from Example 14 and 53 mg (0.161 mmol) of caesium carbonate were suspended in 1 ml of dimethylformamide and admixed with 26 μl (0.161 mmol) of 3-bromo-1,1,1-trifluoro-2-propanol. The mixture was stirred at 75° C. for 8 hours. The suspension was diluted with saturated aqueous ammonium chloride solution. It was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. The crude product was purified by preparative HPLC [Method 5]. This gave 22 mg (36% of theory) of the target compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C1CCCCC=1>>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[NH:11][N:10]=[C:9]2[C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1
Reactant: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Cc1cccc2c(-c3ccc(O)cc3)n[nH]c12
Yield: 74.3 %

Procedure:
Prepared according to Method D step C from 3-(4-methoxyphenyl)-7-methyl-1H-indazole (0.10 g, 0.42 mmol), boron tribromide (0.159 mL, 1.68 mmol) and 0.5 mL of cyclohexene to give the product (0.070 g) as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:32]4[N:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(Nc3ncnc4ccc(-c5ncccn5)cc34)cc2)cc1
Yield: 40.3 %

Procedure:
The (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (200 mg, 0.49 mmol), 2-(tributylstannyl)pyrimidine (200 mg, 0.54 mmol) and bis(triphenylphosphine)palladium(II) chloride (catalytic) were dissolved in dioxan (3 ml) and heated at reflux under nitrogen for 27 hr (Procedure B). The solvent was removed from the cooled reaction under vacuum, and the residue was purified by flash column chromatography (silica gel, eluting with an ethyl acetate/iso-hexane gradient). The resulting oily solid was triturated with iso-hexane/ethyl acetate to give the product (80 mg, 40%) as a pale yellow solid; δH [2H6]-DMSO 10.30 (1H, b, NH), 9.61 (1H, s, 5-H), 9.07 (2H, d, pyrimidine 4-H, pyrimidine 6-H), 8.86 (1H, d, 7-H), 8.51 (1H, s, 2-H), 7.93 (1H, d, 8-H), 7.78 (2H, d, 2′-H, 6′-H), 7.65-7.36 (6H, m, 5×Ph-H, pyrimidine 5-H), 7.11 (2H, d, 3′-H, 5′-H), 5.18 (2H, s, CH2); m/z 406 (M+1)+.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH:6]([NH:34][C:35]([CH2:37][CH2:38][CH2:39][C:40]([O:42]C)=[O:41])=[O:36])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])=[N:21][C:20]=3[CH:32]=2)=[CH:9][CH:8]=1)=[O:4].[OH-].[Na+]>O1CCCC1>[C:3]([CH2:5][CH:6]([NH:34][C:35]([CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])=[N:21][C:20]=3[CH:32]=2)=[CH:9][CH:8]=1)([OH:4])=[O:2]
Reactant: COC(=O)CCCC(=O)NC(CC(=O)OC)c1ccc(NC(=O)Cc2ccc3oc(Nc4ccccc4C)nc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1nc2cc(CC(=O)Nc3ccc(C(CC(=O)O)NC(=O)CCCC(=O)O)cc3)ccc2o1
Reaction time: 3 h
Yield: 44 %

Procedure:
A mixture of methyl 4-(2-methoxycarbonyl-1-{4-[2-(2-o-tolylamino-benzoxazol-5-yl)-acetylamino]-phenyl}-ethylcarbamoyl)-butyrate (0.31 g, Reference Example 12) aqueous sodium hydroxide solution (2.64 ml, 1M) and tetrahydrofuran was heated at reflux temperature for 3 hours. The mixture was then treated with a further aliquot of aqueous sodium hydroxide solution (2.64 ml, 1M) and heating at reflux temperature was continued for a further 3 hours. The reaction mixture was evaporated and the residue was dissolved in water. The pH of this solution was adjusted to 1-2 by addition of concentrated 1,57 hydrochloric acid. The resulting solid was filtered, then washed well with water, then dried and then recrystallised from aqueous iso-butanol. The crystalline solid was washed with pentane and then dried at 100° C. under vacuum to give the title compound (0.13 g) as colourless crystals, m.p. 255.6-257.1° C. [Elemental analysis: Found: C, 64.51; H, 5.41; N, 10.03; H2O, 1.58%. Calculated for C30H30N4O7.0.5H2O: C, 63.43; H, 5.51; N, 9.87; H2O, 1.59%].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:48]([O:52][C:53]([C@@H:55]1[CH2:59][CH2:58][CH2:57][N:56]1[CH2:60][CH2:61]O)=[O:54])([CH3:51])([CH3:50])[CH3:49]>O1CCCC1.CCCCCCC>[C:48]([O:52][C:53]([C@@H:55]1[CH2:59][CH2:58][CH2:57][N:56]1[CH2:60][CH2:61][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)=[O:54])([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CCO
Reactant: Oc1ccc(Br)cc1Sc1cccc(F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1CCOc1ccc(Br)cc1Sc1cccc(F)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-Bromo-2-(3-fluoro-phenylsulfanyl)-phenol (2.898 g, 9.69 mmol) and triphenylphosphine (3.558 g, 13.6 mmol) was dissolved in tetrahydrofuran (70 mL) and cooled to 0° C. under an inert atmosphere. To the solution was added DEAD (2.81 mL, 14.27 mmol)dropwise. After 25 minutes was added 1-(2-hydroxy-ethyl)-pyrrolidine-2-(S)-carboxylic acid tertbutyl ester (2.504 g, 1.163 mmol) in THF (15 mL) via cannulation. The mixture was stirred at room temperature for 16 hours. Heptane (350 mL) and THF (100 mL) was added. The organic phase was then washed with water (4×50 mL) and then brine, dried (Na2SO4), filtered and the filtrate concentrated in the presence of silica gel. The crude products absorbed onto silica gel and eluted with a gradient of heptane-heptane ethyl acetate (85:15). The product was isolated after concentration of relevant fractions.