Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O:37]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]([CH2:18][C:19]1[CH:27]=[C:26]([CH3:28])[C:25]2[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:24]=2)[CH:20]=1)[C:4](=[O:17])[N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1.[C:48]1([C:54]2[NH:55][C:56](=[O:65])[N:57]([CH:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)[CH:58]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[O:65]=[C:56]1[NH:55][C:54]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[CH:58][N:57]1[CH:59]1[CH2:60][CH2:61][N:62]([C:1]([O:2][C@H:3]([CH2:18][C:19]2[CH:27]=[C:26]([CH3:28])[C:25]3[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:34])[CH3:36])[N:24]=3)[CH:20]=2)[C:4](=[O:17])[N:5]2[CH2:10][CH2:9][CH:8]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:7][CH2:6]2)=[O:37])[CH2:63][CH2:64]1
Reactant: O=c1[nH]c(-c2ccccc2)cn1C1CCNCC1
Reactant: Cc1cc(C[C@@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3cc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl 4-nitrophenyl carbonate (150 mg, 0.23 mmol) and 4-phenyl-(piperidin-4-yl)-1H-imidazol-2(3H)-one (PCT Int. Appl. 1998, WO 9811128 A1) (82.2 mg, 1.50 equiv) in dimethylformamide (1 mL) was added diisopropylethylamine (79 μL, 0.45 mmol) and stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography to give 74 mg (43%) as a colorless film. Mass spec.: 770.57 (MH)+.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[O:23]1[CH2:24][CH2:25][N:20]([C:2]2[CH:11]=[C:10]3[C:5]([NH:6][C:7](=[O:16])[C:8]4[N:9]3[C:12](=[O:15])[NH:13][N:14]=4)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH2:21][CH2:22]1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2n2c(=O)[nH]nc12
Reactant: C1COCCN1
Product: O=c1[nH]c2cc([N+](=O)[O-])c(N3CCOCC3)cc2n2c(=O)[nH]nc12

Procedure:
The title compound was prepared from 8-fluoro-7-nitro[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione and morpholine by a method analogous to the method described in example 11. M.p. 250° C. decomp.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:16])[NH:11][C:12]([CH3:15])=[CH:13][CH:14]=1.[OH-].[K+].Cl[CH:20]([F:22])[F:21]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:16])[N:11]([CH:20]([F:22])[F:21])[C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2Cl)c(=O)[nH]1
Reactant: FC(F)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(Cl)cc2Cl)c(=O)n1C(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.0 g of 3-(2,4-dichlorophenyl)-6-methyl-2(1H)-pyridone, 0.8 g of tetrabutylammonium bromide and 2.6 g of potassium hydroxide were dissolved in 100 ml of THF, and chlorodifluoromethane was blown therein under cooling to 0° C. After completion of the blowing, stirring was continued further at room temperature for 1 hour to complete the reaction. Then, the solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate and washed with water. Then, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained crude product was purified by silica gel column chromatography to obtain 0.70 (yield: 14%) of the desired product. Melting point: 83-85° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[CH:12]=1)([CH3:10])[CH3:9]>ClCCl>[CH:8]([C:11]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:19])=[O:18])[CH:12]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ccn(CC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccn(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.6 %

Procedure:
Trifluoroacetic acid (1.20 mL, 15.70 mmol) was added to a solution of tert-butyl 2-(3-isopropyl-pyrrol-1-yl)acetate (350 mg, 1.57 mmol) in dichloromethane at 0° C. and the reaction mixture was stirred at ambient temperature for 16 h. The solvent was evaporated in vacuo and the residue was basified with saturated sodium bicarbonate solution. The solution was washed with diethyl ether and the alkaline solution was then acidified with concentrated aqueous HCl and extracted with diethyl ether. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give 2-(3-isopropylpyrrol-1-yl)acetic acid (180 mg, 69%) as a semi-solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:35][CH:36]([OH:40])[CH2:37][O:38][CH3:39].[I-].[Na+]>CN(C)C=O.O.C(Cl)Cl>[CH:23]([N:18]1[C:17]([C:11]2[S:12][C:13]3[CH2:14][CH2:15][O:16][C:7]4[CH:6]=[C:5]([CH:3]5[CH2:4][N:1]([CH2:35][CH:36]([OH:40])[CH2:37][O:38][CH3:39])[CH2:2]5)[CH:27]=[CH:26][C:8]=4[C:9]=3[N:10]=2)=[N:21][C:20]([CH3:22])=[N:19]1)([CH3:25])[CH3:24]
Reactant: COCC(O)CCl
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COCC(O)CN1CC(c2ccc3c(c2)OCCc2sc(-c4nc(C)nn4C(C)C)nc2-3)C1
Temperature: 50 °C

Procedure:
To a solution of 8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, from Example 519, (0.300 g, 0.000786 mol) and cesium carbonate (0.384 g, 0.00118 mol) in N,N-dimethylformamide (7.9 mL) was added 1-chloro-3-methoxy-2-propanol (0.0844 mL, 0.786 mmol) dropwise. The reaction was heated to 50° C. overnight. Sodium iodide (0.236 g, 0.00157 mol) was added and stirring was continued at 50° C. The mixture was diluted with water and methylene chloride and extracted 3 times with methylene chloride. Purify by flash chromatography then reverse-phase HPLC to obtain 520 as a white solid (22.5 mg). MS (ESI+) 470.2
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH2:8][N:9]2[C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:4][CH:3]=1.C(O)C.Cl.[OH:26][NH2:27].N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[N:27][OH:26])[CH2:7][CH2:8][N:9]2[C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(=O)N1CCC(=O)c2ccc(Cl)cc21
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C(=O)N1CCC(=NO)c2ccc(Cl)cc21
Yield: 86.9 %

Procedure:
To a mixture of 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4-(1H)-quinolinone (14.9 g), obtained in example 1, and ethanol (250 ml) were added hydroxyl amine hydrochloride (7 g) and pyridine (8.5 g), and the mixture was heated under reflux for 1.5 hours. After cooling, the reaction mixture was poured into 1000 ml of water, and precipitated crystals were separated by filtration, washed, dried and recrystallized with ethanol to obtain 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone-4-oxime (yield 13.6 g) as white crystal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([C:23]#[C:24][Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[OH:16][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]1)([CH3:15])[C:24]#[C:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Br[Mg]C#Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(C)(O)C#Cc2ccccc2)CC1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
Into a solution of 4-acetylpiperidine-1-carboxylic acid tert-butyl ester (0.67 g, 2.95 mmol), prepared as described in WO2004041777, in THF (20 mL) cooled at −10° C. was dropped a 1M solution of phenylethynylmagnesium bromide in THF (4.5 mL, 4.5 mmol). The reaction mixture was stirred at room temperature overnight. Afterwards, it was quenched with a saturated aq. solution of ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc 7:3, affording the title product as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=O)([O-:3])=[O:2].ON1C2C=CC=CC=2N=N1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[CH2:33][NH:32][CH2:31][CH2:30]2.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[CH2:33][N:32]([C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:12]=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:31][CH2:30]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(C(=O)C=Cc1cccc([N+](=O)[O-])c1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.9 %

Procedure:
A mixture of 3-nitrocinnamic acid (10 g) and 1-hydroxybenzotriazole (8.2 g) in DMF (100 ml) was stirred at room temperature for 10 min. 1,2,3,4-Tetrahydro-6,7-dimethoxy-isoquinoline (10 g) was then added, followed by dicyclohexylcarbodiimide (10.6 g) and the mixture was stirred at 50° for 48 h and then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide and extracted with dichloromethane. The dried organic extract was evaporated and purified by column chromatography eluting with dichloromethane/methanol (97:3) to give the title compound (7.8 g). NMR includes a signal at d 3.85 (6H,s,OCH3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2.C([Li])CCC.[CH:19]12S[CH:20]1[CH:21]1[S:25][CH:22]1[CH:23]=[CH:24]2>C1COCC1>[CH3:12][C:7]1([CH3:13])[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([S:25][C:22]3[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=3)[CH:3]=2)[O:8]1
Reactant: C1=CC2SC2C2SC12
Reactant: CC1(C)C=Cc2cc(Br)ccc2O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)C=Cc2cc(Sc3ccccc3)ccc2O1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
6-Bromo-2,2-dimethyl-2H-chromene (10 mmoL) in THF (20 mL) was treated with n-butyl lithium (15 mmoL) dropwise at −78° C. The resulting solution was stirred at −78° C. for 30 min. Benzene disulfide (10 mmoL) in THF (10 mL) was then added dropwise into the reaction over about 15 min. The reaction mixture was kept at −78° C. and slowly warmed to room temperature over 2 hrs. The solvent was removed and the residue was partitioned between diethyl ether and water. The combined organic layer was washed with brine, filtered, dried over anhydrous Na2SO4 and concentrated to yield crude material, which was purified by silica gel chromatography to yield the title compound as a white solid.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=O)([CH3:3])[CH3:2].[N-:21]=[C:22]=[O:23].[K+].C(O)(=O)C>O>[CH:1]([N:4]1[C:5]2[C:6](=[CH:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:21][C:22]1=[O:23])([CH3:3])[CH3:2]
Reactant: [N-]=C=O
Reactant: Cc1ccc(C(=O)c2ccc(F)cc2)c(NC(C)C)c1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2c(-c3ccc(F)cc3)nc(=O)n(C(C)C)c2c1

Procedure:
A solution of 8.5 g. of 2-isopropylamino-4-methyl-4'-fluoro-benzophenone and 4.2 g. of potassium isocyanate in 100 ml. of glacial acetic acid is stirred at 60°-70°C. for 20 hours. The resulting mixture is treated with a mixture of ice and water and extracted three times with methylene chloride. The organic phases are combined, washed twice with water, once with sodium bicarbonate solution and again with water followed by drying and evaporation in vacuo. The residue is dissolved in a small amount of methylene chloride and precipitated by adding pentane. The resulting solid is redissolved in methylene chloride, treated with charcoal and diethyl ether exchanged for the methylene chloride to obtain a solid which is dried in a high vacuum at 60°C. to yield 1-isopropyl-7-methyl-4-(p-fluorophenyl)-2(1H)-quinazolinone, m.p. 172°-174°C.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([O:17][C@H:18]([CH3:23])[C:19](OC)=[O:20])[CH:11]=3)=[O:5])[CH2:3][CH2:2]1.[AlH4-].[Li+]>O1CCCC1>[OH:20][CH2:19][C@H:18]([O:17][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[C:7]([NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[N:8]=[CH:9]2)=[CH:14][CH:13]=1)[CH3:23]
Reactant: COC(=O)[C@@H](C)Oc1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CO)Oc1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: -78 °C
Yield: 43.2 %

Procedure:
To a solution of (R)-methyl 2-(3-(cyclopropanecarboxamido)isoquinolin-7-yloxy)propanoate (0.301 mmol, 0.301 mmol) in tetrahydrofuran (5.0 mL, 62 mmol) at −78° C. was added 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (0.40 mL). The reaction mixture was cooled at −78° C. for one hour, and then stirred at room temperature for an additional hour. The reaction mixture was quenched by sequential addition of 20 μL water, then 20 μL 15% aq NaOH, then 60 μL water. The resulting mixture was stirred at room temperature for 15 minutes, then diluted with dichloromethane, dried over MgSO4, filtered through celite, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 37.2 mg (43%) of (R)—N-(7-(1-hydroxypropan-2-yloxy)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=3.213, M+H=287.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.98 (s, 1H), 8.36 (s, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.34 (dd, J=9.0, 2.4 Hz, 1H), 4.89 (s, 1H), 4.58 (dd, J=11.2, 5.7 Hz, 1H), 3.56 (t, J=15.1 Hz, 2H), 2.04 (td, J=7.7, 3.9 Hz, 1H), 1.28 (d, J=6.1 Hz, 3H), 0.89-0.71 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][NH:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]([CH3:31])[CH2:33][CH2:34][N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:29])([F:30])[F:28])[CH:3]=1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNCCN1CCCC1
Product: CN(CCN1CCCC1)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[methyl-(2-pyrrolidin-1-yl-ethyl)amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and methyl-(2-pyrrolidin-1-yl-ethyl)-amine following General Procedure B.
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:50][CH2:51][C:52]1[C:53]([OH:60])=[N:54][C:55]([CH3:59])=[CH:56][C:57]=1[CH3:58]>ClCCl>[OH:60][C:53]1[C:52]([CH2:51][NH:50][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH2:9][N:2]([CH3:1])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:18][CH:17]=2)=[C:57]([CH3:58])[CH:56]=[C:55]([CH3:59])[N:54]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CN(Cc1ccc(C(=O)O)cc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(CN(C)c3ccccc3)cc2)c(O)n1
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
To a solution of 4-((methyl(phenyl)amino)methyl)benzoic acid (200 mg, 0.83 mmol) in dichloromethane (50 mL) were added o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (380 mg, 1 mmol) and triethylamine (202 mg, 2 mmol). The mixture was stirred for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (120 mg, 0.8 mmol) was added and the mixture was stirred at room temperature for 4 hours. The mixture was washed with water (50 mL) and the organic phase was separated, concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) and to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-((methyl(phenyl)amino)methyl)benzamide (50 mg, 16%) as white solid. LRMS (M+H+) m/z: calcd 375.19. found 375. HPLC purity (214 nm): 96%. 1H NMR (300 MHz, CD3OD): δ 7.73 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.15-7.13 (m, 2H), 6.74-6.70 (m, 3H), 6.10 (s, 1H), 4.57 (s, 2H), 4.47 (s, 2H), 3.01 (s. 3H), 2.35 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:34]=[C:33]3[C:29]([CH:30]=[N:31][NH:32]3)=[CH:28][CH:27]=2)O1>>[NH:32]1[C:33]2[C:29](=[CH:28][CH:27]=[C:26]([C:2]3[C:3]4[C:4]5[CH:17]=[CH:16][S:15][C:5]=5[C:6](=[O:14])[NH:7][C:8]=4[CH:9]=[CH:10][C:11]=3[O:12][CH3:13])[CH:34]=2)[CH:30]=[N:31]1
Reactant: CC1(C)OB(c2ccc3cn[nH]c3c2)OC1(C)C
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc2cn[nH]c2c1
Yield: 31.5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (100 mg, 0.32 mmol) was reacted with 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (120 mg, 0.48 mmol) to afford the desired product (35 mg, 31%) as brown solid: ESI MS m/z 348 [C18H11N3O2S+H]+.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[N:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=23)[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>S(=O)(=O)(O)O>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:16]2[C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH2:8])[CH:14]=3)=[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][N:18]3[N:17]=2)=[CH:25][CH:26]=1
Reactant: Fc1ccc(-c2nn3c(c2-c2ccnc(NCc4ccccc4)c2)CCCC3)cc1
Agent: O=S(=O)(O)O
Product: Nc1cc(-c2c(-c3ccc(F)cc3)nn3c2CCCC3)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
With ice-cooling, 10 ml of conc. sulphuric acid are added to 1.29 g (1.29 mmol) of N-benzyl-4-[2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl]pyridine-2-amine, and the mixture is stirred at room temperature for 1 h. The reaction mixture is stirred into ice-water, adjusted to pH 10 using cone. NaOH and extracted with 3×50 ml of dichloromethane. The combined organic phases are washed with water, dried over MgSO4 and freed from the solvent under reduced pressure. This gives 239 mg (35%) of the desired product; log P(HCOOH): 1.21; 1H-NMR (DMSO-d6): 7.81 (d, 1H), 7.416 (dd, 2H), 7.15 (dd, 2H), 6.28 (s, 1H), 6.24 (d, 1H), 5.83 (br.s, 2H), 4.15 (dd, 2H), 2.73 (dd, 2H), 2.02 (m, 2H), 1.80 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)([O:13][CH3:14])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[Cl-].[NH4+]>C(Cl)Cl>[F:22][C:17]1[CH:16]=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[C:19]([F:21])[CH:18]=1
Reactant: COC1(c2cc(F)cc(F)c2)CCN(C(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1(c2cc(F)cc(F)c2)CCNC1
Yield: 72.6 %

Procedure:
To a solution of tert-butyl-3-(3,5-difluorophenyl)-3-methoxypyrrolidin-1-carboxylate (2.64 g, 8.4 mmol) in methylene chloride (20 mL), was added trifluoroacetic acid (5 mL). The mixture was stirred for 1 h at ambient temperature after which aqueous saturated ammonium chloride solution (50 ml) was added and the aqueous phase was extracted with methylene chloride (2×50 mL). The combined organic phase was dried (Na2SO4), filtered and evaporated to give the crude product, purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) gave the title compound (1.3 g, 73%). MS m/z (rel. intensity, 70 eV) 213 (M+, 0.5), 183 (bp), 171 (89), 141 (80), 113 (88).
Reaction SMILES: CC1(C)[O:6][C:5](=O)[C@H:4]([C@H:8]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:17][C@H:16]2[CH3:27])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[O:3]1.[NH2:29][OH:30]>CC(O)C.O>[OH:30][NH:29][C:5](=[O:6])[C@@H:4]([OH:3])[C@@H:8]([C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:17][C@H:16]1[CH3:27])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: NO
Reactant: CC(C)C[C@@H](C(=O)N1CCN(c2ccccn2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O
Solvent: CC(C)O
Solvent: O
Product: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)C[C@H]1C)[C@H](O)C(=O)NO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 47.5 %

Procedure:
To a solution of (5S)-2,2-dimethyl-5-((1R)-3-methyl-1-{[(2R)-2-methyl-4-(2-pyridinyl)piperazinyl]carbonyl}butyl)-1,3-dioxolan-4-one (517 mg; 1.33 mmol; 1.0 eq) in iPrOH (2.0 mL) was added an aqueous solution of hydroxylamine (391.5 μl; 6.64 mmol; 5.0 eq.) and the resulting reaction mixture was stirred at RT for 40 min. HPLC analyses showed the presence of 2 diastereoisomers (75/25). This reaction mixture was dissolved in water (6 mL) and directly purified by reverse-phase chromatography (major diastereoisomer as the first eluted peak, gradient starting from 100% H2O up to 75% H2O in ACN in 5 min, then isocratic 75% H2O in ACN for 25 min; flow: 50 mL/min) to give the title product (4) as a white powder (230 mg; 47%). 1H NMR (CD3OD, 300 MHz) δ 8.10 (m, 1H), 7.58 (m, 1H), 6.84 (m, 1H), 6.69 (m, 1H), 4.84-4.70 (m, 1H), 4.60 (m, 1H), 4.48 (m, 0.4H), 4.19 (m, 1H), 4.13-3.98 (m, 2H), 3.71-3.55 (m, 0.6H), 3.30-3.07 (m, 2H), 3.05-2.82 (m, 1H), 1.94-1.76 (m, 1H), 1.55-1.38 (m, 3H), 1.35 (d, 1.3H, J=6.7 Hz), 1.23 (d, 1.7H, J=6.7 Hz), 0.93 (m, 6H). M+(ESI): 365.2, M−(ESI): 363.2. HPLC (Condition B), Rt: 2.4 min (HPLC purity: 97.6
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=CC(O)=C[CH:5]=1.N[C@H](C(O)=O)CCC(=O)O.N[C@H](C(O)=O)CCCNC(=N)N>>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH:4]([CH3:9])[CH3:5]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: N[C@@H](CCC(=O)O)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
Tyr 0.93 (1); Glu 1.04 (1); Arg 0.93 (1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][CH2:8][Mg]Br)=[CH:5][CH:4]=1.CO[C:15]1[CH:23]=CC(CCBr)=C[CH:16]=1.[Mg]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][CH2:8][CH2:23][CH:15]=[CH2:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC[Mg]Br)cc1
Reactant: COc1ccc(CCBr)cc1
Agent: [Mg]
Product: C=CCCCc1ccc(OC)cc1

Procedure:
This compound was prepared as in Example 35a using 4-methoxyphenethyl magnesium bromide prepared from 4-methoxyphenethyl bromide and magnesium turnings. The crude oil isolated after work-up was distilled to give the title compound (b.p. 65° C., 0.3 mm.Hg), as a colourless oil.