Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[C:21]([Cl:26])[CH:20]=3)=[O:16])[CH2:9]1.[N+](C1C=CC([O:36][C:37](=O)[NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]3=[O:51])=[CH:41][C:40]=2[F:52])=CC=1)([O-])=O>>[F:52][C:40]1[CH:41]=[C:42]([N:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]2=[O:51])[CH:43]=[CH:44][C:39]=1[NH:38][C:37]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[C:21]([Cl:26])[CH:20]=3)=[O:16])[CH2:9]1)=[O:36]
Reactant: O=C(NC[C@H]1CCNC1)c1cc2ccc(Cl)cc2[nH]1
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1cc2ccc(Cl)cc2[nH]1

Procedure:
68.3 Using general method H, 6-chloro-1H-indole-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give 6-chloro-1H-indole-2-carboxylic acid {(R)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidin-3-ylmethyl}-amide. Pale yellow solid. MS 506.1 ([M−H]−)
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH2:22][CH2:23][CH3:24])[O:11][C:10](=[O:12])[C:9]([O:13]CC3C=CC=CC=3)=[C:8]2[OH:21])=[CH:3][CH:2]=1.OC1C(=O)OC(C)(C2C=CC=CC=2)C=1O>>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH2:22][CH2:23][CH3:24])[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[OH:21])=[CH:3][CH:2]=1
Reactant: CCCC1(c2ccc(-c3ccccc3)cc2)OC(=O)C(OCc2ccccc2)=C1O
Agent: CC1(c2ccccc2)OC(=O)C(O)=C1O
Product: CCCC1(c2ccc(-c3ccccc3)cc2)OC(=O)C(O)=C1O
Yield: 51.6 %

Procedure:
Hydrogenolysis of 250 mg of 5-[(1,1'-biphenyl)-4-yl]-4-hydroxy-3-phenylmethoxy-5-propyl-2(5H)-furanone was performed in a similar manner as described in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provided 100 mg (52% yield) of a white powder: mp 203-204° C. dec.(acetone/CHCl3 /hexanes). 1H NMR (acetone-d6) δ 7.65-7.40 (m, 9H), 2.25-1.95 (m, 2H), 1.45-1.10 (m, 2H), 0.95 (t, J=6.9 Hz, 3H). Anal Calcd for C19H18O4 +0.125 H2O: C, 73.01; H, 5.88. Found: C, 72.99; H, 5.86.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Br:13])[CH:7]=1)[CH3:2].[H-].[Na+].IC.[CH3:19]COC(C)=O>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Br:13])[CH:7]=1)[CH3:19])[CH3:2]
Reactant: CCOC(=O)Cc1cc(Cl)cc(Br)c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1cc(Cl)cc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of (3-bromo-5-chloro-phenyl)-acetic acid ethyl ester (5.0 g, 18.0 mmol) in DMF (50 mL) at 0° C. under N2 was added sodium hydride (60% in mineral oil; 0.8 g, 19.8 mmol), and the mixture was warmed to room temperature over 15 minutes. Iodomethane (1.3 mL, 19.8 mmol) was added, and the reaction was monitored by analytical LCMS. Once the reaction was complete, the mixture was worked-up with EtOAc and H2O, and the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([NH2:13])=[O:12].[Cl:14][S:15](O)(=[O:17])=[O:16]>>[C:11]([CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([S:15]([Cl:14])(=[O:17])=[O:16])[CH:6]=2)[O:1]1)(=[O:12])[NH2:13]
Reactant: NC(=O)C1CCc2ccccc2O1
Reactant: O=S(=O)(O)Cl
Product: NC(=O)C1CCc2cc(S(=O)(=O)Cl)ccc2O1
Temperature: 0 °C
Yield: 73 %

Procedure:
The compound from Example 21 (2.0 g, 11.3 mmol) was added in portions over 10 minutes to cooled (0° C.) chlorosulfonic acid (9 mL). After 75 minutes the mixture was added slowly and dropwise to ice (150 g). The mixture was filtered and the solids washed with water (3×20 mL) and dried at 50° C. in vacuo to give a colorless powder (2.29 g, 73%). Mp 147-148° C.; 1H NMR (CDCl3, 300 MHz) δ 7.82 (m, 2H), 7.08 (d, J=8.6 Hz, 1H), 6.50 (br s, 1H), 5.77 (br s, 1H), 4.68 (dd, J=9.4 Hz, 3.1 Hz, 1H), 2.95 (m, 2H), 2.52 (m, 1H), 2.16 (m, 1H).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[N:16]1([C:21]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[N:17]1>>[CH3:7][N:6]1[C:2]([C:24]2[CH:23]=[CH:22][C:21]([N:16]3[CH:20]=[CH:19][CH:18]=[N:17]3)=[CH:26][CH:25]=2)=[C:3]([C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[N:4]=[CH:5]1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(-n2cccn2)cc1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(-n2cccn2)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-pyrazol-1-yl-phenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C19H14N6, 327. Found, 327.
Reaction SMILES: C[Sn](C)(C)[C:3]1([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4]1.Cl[B:15]([CH2:18][CH3:19])[CH2:16][CH3:17]>>[CH2:16]([B:15]([CH2:18][CH3:19])[C:3]1([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4]1)[CH3:17]
Reactant: CCB(Cl)CC
Reactant: C[Si](C)(C)C1([Sn](C)(C)C)C=CC=C1
Product: CCB(CC)C1([Si](C)(C)C)C=CC=C1
Reaction time: 2 h

Procedure:
To 5.44 g (18.1 mmol) of colorless neat trimethyl(trimethylsilylcyclopentadienyl)tin is added 1.89 g (2.28 ml, 18.1 mmol) of colorless chlorodiethylborane at once at room temperature. An intense yellow color immediately appears. The mixture is stirred for 2 h and then subjected to fractional distillation. At a bath temperature of 60° C., the major part of the chlorotrimethylstannane can be separated off as the first fraction.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6]O)([O-:3])=[O:2].C(Cl)(Cl)Cl.P(Br)(Br)[Br:18]>O>[N+:1]([C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6][Br:18])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CO
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(Cl)ccc1CBr
Yield: 80 %

Procedure:
To a solution of 16.5 g. of 2-nitro-4-chlorobenzyl alcohol in 200 ml. of chloroform was added dropwise 13 g. of phosphorus tribromide, and the mixture was heated to reflux for 1 hour on a water bath. The reaction mixture was then poured into water, and the chloroform layer was separated and washed with water. After the solvent was removed, the residue was extracted with ligroin while warming and allowed to stand to form colorless acicular crystals of 2-nitro-4-chlorobenzyl bromide (80% yield) melting at 42° to 43° C.
Reaction SMILES: O.C(O)(=O)C.[S:6]([N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][CH2:19][C:18](=[O:27])[CH2:17]1)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[C-:28]#[N:29].[Na+]>C(O)C>[OH:27][C:18]1([C:28]#[N:29])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:16]([S:6]([C:9]2[CH:10]=[CH:11][C:12]([CH3:13])=[CH:14][CH:15]=2)(=[O:7])=[O:8])[CH2:17]1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)N2CC(=O)CCc3ccccc32)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CC(O)(C#N)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 64.5 %

Procedure:
30 ml of water, 40 ml of acetic acid and 20 g of 1,2,4,5-tetrahydro-N-tosyl-[3H]-1-benzazepine-3-one [J. Chem. So., Vol. C (1970), p.2192] were successively added to 300 ml of ethanol and then 20 g of sodium cyanide were added thereto over 2 minutes. The mixture was stirred for 4 hours at room temperature and was then concentrated to 100 ml under reduced pressure. The mixture was extracted with ether and the ether extracts were washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 21 g of raw product which was crystallized from a minimum of ether. The mixture was vacuum filtered to obtain 14 g of 3-hydroxy-1-(4-methylphenylsulfonyl)-1,2,4,5-tetrahydro-[3H]-1-benzazepine-3-carbonitrile in the form of colorless crystals melting at 128°C.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][Br:5].N1C=CN=C1.[C:12]([Si:16]([CH3:19])([CH3:18])Cl)([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[Br:1][CH2:2][CH:3]([CH2:4][Br:5])[O:6][Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC(CBr)CBr
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(CBr)CBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
26.7 g (122.4 mmol) of 1,3-dibromopropan-2-ol are dissolved in 150 ml of DCM, and 18.35 g (269.59 mmol) of imidazole are added. 18.47 g (122.54 mmol) of tert-butyldimethylchlorosilane in 150 ml of DCM are subsequently added dropwise. The mixture is left to stir at RT for 18 h, subjected to conventional work-up, giving, as crude product, 39.1 g (Y=95.9%) of step 1 as colourless oil, which is employed directly in step 2.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=C.C(O)(=[O:31])CCCCCCC/C=C\CCCCCCCC>C(O)(=O)C>[C:2]([C:1]([O:11][CH3:12])=[O:10])(=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=C(C(=O)OC)c1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccccc1
Yield: 88 %

Procedure:
The co-oxidation reaction was carried out in manner as described in Example 16, except that methyl atropate was used in lieu of oleic acid. As a result, acetic acid was obtained at a yield of 95% and methyl benzoylformate was obtained at a yield of 88%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23](=[O:24])[C:22]3[NH:21][C:20](C4C=CC(I)=CC=4)=[N:19][C:18]=3[N:17]([CH2:32][CH2:33][CH3:34])[C:16]2=[O:35])=[CH:11][CH:10]=1.B(O)O.CC[N:41]([CH2:44][CH3:45])CC>CC([O-])=O.CC([O-])=O.[Cu+2].C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23](=[O:24])[C:22]3[N:21]([C:4]4[CH:5]=[C:45]([CH:7]=[CH:8][CH:3]=4)[C:44]#[N:41])[CH:20]=[N:19][C:18]=3[N:17]([CH2:32][CH2:33][CH3:34])[C:16]2=[O:35])=[CH:11][CH:10]=1
Reactant: CCCn1c(=O)n(-c2ccc(-c3ccccc3SC)cc2)c(=O)c2[nH]c(-c3ccc(I)cc3)nc21
Reactant: CCN(CC)CC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: ClCCl
Product: CCCn1c(=O)n(-c2ccc(-c3ccccc3SC)cc2)c(=O)c2c1ncn2-c1cccc(C#N)c1
Reaction time: 12 h
Yield: 88.1 %

Procedure:
A 25-mL round bottom flask equipped with a stir bar was charged with 6 (180 mg, 0.46 mmol) and CH2Cl2 (5.0 mL). The reaction mixture was treated with boronic acid 7 (135 mg, 0.92 mmol), Et3N (0.13 mL, 0.92 mmol), crushed 4 A mol. sieves (720 mg, 4× weight) and Cu(OAc)2 (167 mg, 0.92 mmol) at 25° C. After 12 h, the reaction was filtered through a plug of Celite® and washed with CH2Cl2 (100 mL). The organic phase was washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography of the residue on silica (40-50% EtOAc/hexanes) provided 8 (100 mg, 44%) as a white solid: ESI-MS m/z: [C28H23N5O2S+H]+ 494; 1H NMR (300 MHz, CDCl3) δ 7.90-7.00 (m, 13H), 4.19 (t, J 7.5 Hz, 2H), 2.33 (s, 3H), 1.99-1.85 (m, 2H), 1.03 (t, J=7.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]3[O:22][C:23]([NH:26][CH:27]([CH3:29])[CH3:28])=[N:24][N:25]=3)[CH:19]=2)[N:14](S(C2C=CC(C)=CC=2)(=O)=O)[CH:13]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]3[O:22][C:23]([NH:26][CH:27]([CH3:29])[CH3:28])=[N:24][N:25]=3)[CH:19]=2)[NH:14][CH:13]=1
Reactant: CNC(=O)c1ccc(F)c(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4nnc(NC(C)C)o4)cc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(F)c(-c2c[nH]c3ccc(-c4nnc(NC(C)C)o4)cc23)c1
Temperature: 90 °C
Yield: 12.8 %

Procedure:
To a solution of 4-fluoro-3-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)-N-methylbenzamide (250 mg, 0.457 mmol) in 1,4-dioxane (5 mL) was added aq. NaOH (7 M, 5 mL) and the reaction was heated at 90° C. for 1 h. The reaction was then quenched with water to get a precipitate. The precipitate was filtered and washed with water (2×100 mL) and dried. The crude product was purified with preparative HPLC (eluted with 20-80% MeCN in water with 0.1% TFA in each solvent) to give 4-fluoro-3-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1H-indol-3-yl)-N-methylbenzamide (23 mg, 12%). MS (ESI, pos. ion) m/z: 394.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.56 (d, 1H, J=4.8 Hz), 8.16 (dd, 1H, J=7.2, 2.4 Hz), 8.01 (s, 1H), 7.81-7.84 (m, 2H), 7.70 (dd, 1H, J=8.8, 1.2 Hz), 7.60-7.63 (m, 2H), 7.46 (dd, 1H, J=10.4, 8.8 Hz), 3.68-3.76 (m, 1H), 2.81 (d, 3H, J=4.4 Hz), 1.20 (d, 6H, J=6.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.COC1C=CC(C[N:31]2[C:35]3=[N:36][CH:37]=[CH:38][C:39]([O:40][C:41]4[C:46]([F:47])=[CH:45][C:44]([NH2:48])=[C:43]([F:49])[CH:42]=4)=[C:34]3[C:33]([CH3:50])=[N:32]2)=CC=1.C(N(CC)CC)C>CN(C=O)C.CN(C)C1C=CN=CC=1.O.C(Cl)Cl>[F:49][C:43]1[CH:42]=[C:41]([O:40][C:39]2[CH:38]=[CH:37][N:36]=[C:35]3[NH:31][N:32]=[C:33]([CH3:50])[C:34]=23)[C:46]([F:47])=[CH:45][C:44]=1[NH:48][C:15]([C:12]1[C:13](=[O:14])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=[CH:10][CH:11]=1)=[O:17]
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4cc(F)c(N)cc4F)ccnc32)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1n[nH]c2nccc(Oc3cc(F)c(NC(=O)c4ccnn(-c5ccc(F)cc5)c4=O)cc3F)c12
Temperature: 70 °C
Reaction time: 1 h
Yield: 211.8 %

Procedure:
Charge a 100 mL round-bottomed flask with 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (0.103 g, 0.442 mmol obtained from Example 19, step C), and CH2Cl2 (10 mL). Oxalyl chloride in DCM (2M) (2.84 ml, 5.68 mmol) and DMF (3 drops) were added. The reaction mixture was stirred for 1 hour and concentrated. The crude material was resuspend in DCM and 4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2,5-difluorobenzenamine (0.750 g, 1.89 mmol), N,N-dimethylpyridin-4-amine (0.0231 g, 0.189 mmol) and triethylamine (0.287 g, 2.84 mmol) were added. The reaction mixture was stirred at r ambient temperature for 16 hours, then diluted with water and DCM. The organic layer washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by chromatography, eluting with EtOAc and concentrated. To the crude material in a 25 mL RBF was add TFA (3 mL). The mixture was heated to 70° C. for 2 hours, then cooled to ambient temperature and concentrated. The residue was triturated with DCM/MeOH 1:1 (5 mL) to afford 461 mg (46%) of the desired product. LRMS M+1 (493.1) observed. 1H NMR (400 MHz, DMSOd6) δ12.14 (s, 1H), 8.54 (s, 1H), 8.43 (m, 1H), 8.36 (m, 1H), 8.30 (m, 1H), 7.77 (m, 1H), 7.68 (m, 2H), 7.42 (t, J=8 Hz, 2H), 6.35 (d, J=5 Hz, 1H), 2.62 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][O:7][CH2:8][CH:9]([OH:20])[CH2:10][CH2:11][CH2:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16].[CH:21](=O)[CH2:22][CH3:23]>C1(C)C=CC=CC=1>[CH2:22]([CH:23]1[N:4]([CH2:5][CH2:6][O:7][CH2:8][CH:9]([OH:20])[CH2:10][CH2:11][CH2:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH2:3][CH2:2][O:1]1)[CH3:21]
Reactant: CCCC(CCC)CCCC(O)COCCNCCO
Reactant: CCC=O
Solvent: Cc1ccccc1
Product: CCCC(CCC)CCCC(O)COCCN1CCOC1CC
Temperature: 25 °C
Yield: 100 %

Procedure:
To a 10 mL flask containing 1-[2-(2-hydroxy-ethylamino)-ethoxy]-6-propyl-nonan-2-ol (510 mg, 1.76 mmol, 1 eq.) in toluene (3 mL) was added dropwise at room temperature propionaldehyde (0.14 mL 1.85 mmol, 1.05 eq., d=0.798) before heating to reflux with a Dean-Stark trap for 2 h. The reaction was cooled to room temperature and concentrated to afford the title compound as 2 stereoisomers (50:50) (580 mg, 100% yield). 1H NMR (CDCl3, 400 MHz) d?(ppm): 4.09-4.03 (m, H); 3.92-3.81 (m, 2H); 3.81-3.73 (m, H); 3.73-3.50 (m, 2H+2H); 3.35-3.21 (m, 2H); 2.92-2.74 (m, 2H); 2.72-2.63 (m, H); 2.62-2.52 (m, H); 1.69-1.14 (m, 15H+2H); 0.96 (m, 3H); 0.87 (t, J=7.0 Hz, 6H). 13C NMR (CDCl3, 129.9 MHz) d?(ppm): 98.0; 97.9; 76.1; 75.7; 70.6 (2C); 70.2 (2C); 64.2 (2C); 53.2; 53.1; 52.6 (2C); 36.9 (2C); 36.0 (2C+2C); 33.7 (2C); 33.6; 33.5; 26.9; 26.8; 22.7 (2C); 19.8 (2C+2C); 14.5 (2C+2C); 9.2 (2C).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:11]=[CH:12][C:3]=12.[CH2:22]([NH2:24])[CH3:23]>>[CH2:22]([NH:24][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:11]=[CH:12][C:3]=12)[CH3:23]
Reactant: CCN
Reactant: COc1ccc(Cn2ncc3c(Cl)c(C=O)cnc32)cc1
Product: CCNc1c(C=O)cnc2c1cnn2Cc1ccc(OC)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 4-chloro-1-(4-methoxy-benzyl)-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (350 mg, 1.16 mmol), ethyl amine (70 wt. % solution in water, 2 mL, 25 mmol) is heated at 120° C. in a sealed tube. After overnight, the reaction mixture is cooled to room temperature and concentrated. The residue is dissolved in HCl solution (1N, 4 mL) and heated at 50° C. After stirring for 1.5 hours, the reaction mixture is basified with saturated sodium bicarbonate solution to pH=8. The solid is collected by filtration and washed with water, then hexanes, dried to afford the title compound as a solid. MS m/z 311.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[C:4]([O:12][CH2:13][CH2:14][O:15][CH3:16])[N:3]=1.C(Cl)Cl.CC(C[AlH]CC(C)C)C>CO>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[C:4]([O:12][CH2:13][CH2:14][O:15][CH3:16])[N:3]=1
Reactant: COCCOc1cc(C(=O)OC)nc(Cl)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: ClCCl
Product: COCCOc1cc(C=O)nc(Cl)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 106 %

Procedure:
A 25 mL round bottomed flask was charged with methyl 2-chloro-6-(2-methoxyethoxy)pyrimidine-4-carboxylate [SAD105-047F1] (45 mg, 1 equiv.) and CH2Cl2 (1 mL). 1 M DIBAL-H (0.2 mL, 1.1 equiv.) was added at −78° C. over 2 min under argon. The reaction mixture was stirred for 3 h at −78° C. but the LC-MS still showed a lot of starting material. Additional 1 M DIBAL-H (0.27 mL, 1.4 equiv.) was added at −78° C. over 2 min under argon and after 0.5 h LC-MS showed no more starting material but mostly 1 peak at 1.20 min (M+1=217, M+1+MeOH=249). The reaction mixture was quenched with MeOH (0.5 mL) and then with 10% NH4Cl (1 mL). The reaction mixture was warmed to RT and then the solvent was concentrated under reduced pressure. The residue was diluted with 10% NH4Cl (4 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide 41.9 mg of the crude 2-chloro-6-(2-methoxyethoxy)pyrimidine-4-carbaldehyde as a yellow oil which was used in the next step without further purification, (H NMR δ: 9.91 (s, 1H); 7.23 (s, 1H); 4.59-4.64 (m, 2H), 3.7-3.8 (m, 2H); 3.44 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:30][CH2:31][S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:10][CH:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[NH:7]1)=[O:5])C.[OH-].[Li+]>>[C:14]1([S:11]([CH:9]2[CH:8]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:27])[CH3:28])=[CH:22][CH:21]=3)[NH:7][C:6]([CH2:30][CH2:31][S:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)(=[O:34])=[O:33])([C:4]([OH:5])=[O:3])[CH2:10]2)(=[O:12])=[O:13])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1(CCS(=O)(=O)c2ccccc2)CC(S(=O)(=O)c2ccccc2)C(c2ccc(C(C)(C)C)cc2)N1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(C2NC(CCS(=O)(=O)c3ccccc3)(C(=O)O)CC2S(=O)(=O)c2ccccc2)cc1

Procedure:
In analogy to the procedure described in example 253e, 4-benzenesulfonyl-2-(2-benzenesulfonyl-ethyl)-5-(4-tert-butyl-phenyl)-pyrrolidine-2-carboxylic acid ethyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow solid which was used in the next step without further purification. MS (ESI): m/z=556.2 [M+H]+.
Reaction SMILES: [OH-].[Na+].[F:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14]C)=[O:13])=[N:10][CH:11]=1.Cl.[Na+].[Cl-]>C1COCC1.O.CCOC(C)=O.O>[F:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1
Reactant: COC(=O)c1ccc(OCF)cn1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OCF)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.9 %

Procedure:
N NaOH (81 μL) was added to a solution containing methyl 5-fluoromethoxypyridine-2-carboxylate (50 mg) in THF/water (2 mL, 3/1), and the mixture was stirred at RT for 10 min. Water (1 mL) was added to the reaction solution, followed by further stirring for 20 min. The reaction solution was made acidic with 5 N hydrochloric acid. EtOAc and a saturated NaCl solution were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous MgSO4, and the insoluble matter was separated by filtration. The filtrate was concentrated to obtain the title compound (22.6 mg). 1H-NMR (CDCl3) δ (ppm): 5.81 (d, J=53.2 Hz, 2H), 7.61 (ddd, J=0.8, 2.8, 8.8 Hz, 1H), 8.25 (d, J=0.8, 8.8 Hz, 1H), 8.42 (d, J=2.4 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][C:13]=3[OH:17])[O:8][C:7]=2[C:19](OCC)=[O:20])=[CH:4][CH:3]=1.[CH3:26][NH2:27]>>[OH:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][C:13]=3[OH:17])[O:8][C:7]=2[C:19]([NH:27][CH3:26])=[O:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(O)cc1
Reactant: CN
Product: CNC(=O)c1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 4',5,7-trihydroxy-2-isoflavonecarboxylate (100 mg) and 30% methanolic solution of methylamine (5 ml) was stirred at room temperature for 30 minutes, the solvent was distilled off under reduced pressure, and the solid residue was recrystallized from methanol, affording 50 mg of 4',5,7-trihydroxy-N-methyl-2-isoflavonecarboxamide.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:44])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH:41]3[CH2:43][CH2:42]3)[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:41]1([C:37]2[CH:36]=[C:35]([C:31]3[CH:30]=[C:29]([C:27]4[CH2:26][C:25](=[O:44])[NH:24][C:9]5[CH:10]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=5[N:7]=4)[CH:34]=[CH:33][CH:32]=3)[CH:40]=[CH:39][N:38]=2)[CH2:42][CH2:43]1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C3CC3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccnc(C4CC4)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-{3-[3-(2-cyclopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M269) (349 mg, 0.55 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (230 mg, 81%).