Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([C:20](O)=[O:21])[C:11]3=[O:23])=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(=O)C([Cl:27])=O.CN(C)C=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([C:20]([Cl:27])=[O:21])[C:11]3=[O:23])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1nc2ccccc2n(-c2ccc3c(c2)OCO3)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1nc2ccccc2n(-c2ccc3c(c2)OCO3)c1=O

Procedure:
5.7 g (19 mmol) of 1-(benzo[d][1,3]dioxol-5-yl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid and 3.1 g (24 mmol) of oxalyl chloride were dissolved in dichloromethane (10 mL), and 0.026 g (0.35 mmol) of dimethylformamide was added thereto. The mixture was heated to reflux for 2 hours while stirring. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure to obtain 1-(benzo[d][1,3]dioxol-5-yl)-2-oxo-1,2-dihydroquinoxaline-3-carbonyl chloride as yellow crystals (Compound No. of Production Intermediate: IX-73).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:26])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=1)=[C:7]2[CH3:25].[CH3:27][O:28][C:29](=[O:32])[CH2:30]Br>>[CH3:27][O:28][C:29](=[O:32])[CH2:30][O:26][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:11]2[C:6]=1[C:7]([CH3:25])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=1)[C:9](=[O:12])[NH:10]2
Reactant: COC(=O)CBr
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(=O)[nH]c2c(F)ccc(O)c12
Product: COC(=O)COc1ccc(F)c2[nH]c(=O)c(Cc3ccc(-n4cccn4)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 7a using 8-fluoro-5-hydroxy-4-methyl-3-(4-pyrazol-1-ylbenzyl)-1H-quinolin-2-one and bromoacetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:12]=3[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:34][CH:33]=[CH:32][CH2:31]4)=[O:29])=[CH:24][CH:23]=3)[C:10](=[O:35])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C([Sn]([N:51]=[N+:52]=[N-:53])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[C:16]([C:19]4[NH:53][N:52]=[N:51][N:20]=4)[CH:17]=[CH:18][C:12]=3[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:31][CH:32]=[CH:33][CH2:34]4)=[O:29])=[CH:24][CH:23]=3)[C:10](=[O:35])[CH2:9]2)=[O:7])=[CH:36][CH:37]=1
Reactant: N#Cc1ccc2c(c1)CN(C(=O)c1ccc(Cl)cc1)CC(=O)N2Cc1ccc(C(=O)N2CC=CC2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3cc(-c4nnn[nH]4)ccc32)cc1)N1CC=CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
26 mg (0.051 mmol) of 4-(4-chlorobenzoyl)-7-cyano-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-1,3,4,5-tetrahydrobenzo[e][1,4]-diazepin-2-on was dissolved in 10 ml of toluene. 0.032 ml (0.11 mmol) of tributyltin azide was added to the obtained solution, and they were stirred at 100° C. overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the solvent was evaporated and the obtained crude product was treated in the same manner as in Step 3 in Example 1 to obtain the title compound.
Reaction SMILES: O1CCOCC1.[OH-].[Li+].[CH:9]1([C:14]([N:16]2[CH2:21][CH:20]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[CH2:19][CH:18]([C:31]([O:33]CC)=[O:32])[CH2:17]2)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1>O>[CH:9]1([C:14]([N:16]2[CH2:21][CH:20]([C:22]3[CH:23]=[CH:24][C:25]([CH:28]([CH3:29])[CH3:30])=[CH:26][CH:27]=3)[CH2:19][CH:18]([C:31]([OH:33])=[O:32])[CH2:17]2)=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)C1CC(c2ccc(C(C)C)cc2)CN(C(=O)C2CCCC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 ml of dioxane, 25 ml of water and 0.63 g (25.8 mmol) of lithium hydroxide were added to 2.40 g (6.46 mmol) of ethyl 1-(cyclopentylcarbonyl)-5-[4-(1-methylethyl)phenyl]piperidine-3-carboxylate. The mixture was stirred at RT overnight. For work-up, the dioxane was removed under reduced pressure, water was added to the reaction mixture and the mixture was acidified using aqueous 1 N hydrochloric acid solution. The mixture was extracted with dichloromethane. The organic phase was dried with sodium sulphate and concentrated under reduced pressure. Yield: 1.65 g (98% of theory)
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[NH2:4].Cl[C:16](=O)[CH2:17][N:18]1[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[N:19]1.O>N1C=CC=CC=1>[F:14][C:11]([F:13])([F:12])[C:7]1[CH:6]=[C:5]([C:3]2[N:4]=[C:16]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[N:19]3)[O:1][N:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NC(=NO)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnn(CC(=O)Cl)c1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)no2)c1
Temperature: 115 °C
Reaction time: 8 h
Yield: 10.1 %

Procedure:
A solution of N′-hydroxy-3-(trifluoromethyl)benzenecarboximidamide (2.1 g) in pyridine (20 mL) was cooled in an ice bath, and the compound (2.3 g) obtained in Example 115c was added. The reaction mixture was stirred overnight with heating at 110-120° C. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was separated, washed successively with 1N hydrochloric acid and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: petroleum ether-ethyl acetate) to give the title compound (0.38 g) as a solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][CH2:19][CH:20]([CH2:22]O)[N:21]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1.N1CCCCC1>[N:36]1([CH2:22][CH:20]2[CH2:19][O:18][C:17]([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:16][CH:15]=3)=[N:21]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: OCC1COC(c2ccc(OCCCN3CCCCC3)cc2)=N1
Reactant: C1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1cc(C2=NC(CN3CCCCC3)CO2)ccc1OCCCN1CCCCC1
Temperature: -23 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a cold (−23° C.) solution of {2-[4-(3-piperidin-1-ylpropoxy)phenyl]-4,5-dihydro-1,3-oxazol-4-yl}methanol ax46 (0.27 g, 0.85 mmol, 1 eq) and triethylamine (0.413 ml, 2.98 mmol, 3.5 eq) in tetrahydrofuran (10 ml) is added methanesulfonyl chloride (0.23 ml, 2.98 mmol, 3.5 eq). The mixture is stirred for 2 h at −23° C., and then, concentrated under vacuum. The residual oil is treated with piperidine (0.08 ml, 0.8 nmol, 2 eq) and triethylamine (0.05 ml, 0.42 mmol, 1 eq) and stirred at 100° C. in a sealed tube overnight. After 24 h, piperidine (1 eq) and triethylamine (1 eq) are added and the mixture is stirred for another 48 h at 100° C. Concentration under vacuum gives 0.33 g of brown oil. The oil is purified on silicagel (eluent: dichloromethane/ethanol/ammonia 92:7.2:0.8) to give 45 mg of 1-(3-{4-[4-(piperidin-1-ylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]phenoxy}propyl)piperidine 20.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])[C:2]([NH2:4])=[S:3].BrBr.C(OCC)C>ClC1C=CC=CC=1>[NH2:4][C:2]1[S:3][C:6]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=[CH:14][C:5]=2[N:1]=1
Reactant: COC(=O)c1cccc(NC(N)=S)c1
Agent: BrBr
Solvent: CCOCC
Solvent: Clc1ccccc1
Product: COC(=O)c1cccc2nc(N)sc12
Reaction time: 4 h
Yield: 83 %

Procedure:
8.4 g of methyl 3-thioureido-benzoate are suspended in 120 ml of chlorobenzene, 2.2 ml of bromine in 30 ml of chlorobenzene are added at 0° C. in the course of 1 hour, while stirring as thoroughly as possible, and the mixture is then stirred to room temperature. It is then kept at 70° C. for 4 hours and subsequently cooled, a little diethyl ether is added and the precipitate is filtered off, mixed thoroughly with 70 ml of aqueous sodium bicarbonate solution, filtered off again and washed with water. 7.7 g (88%) of crude product of melting point 231-232° C. result. HPLC analysis shows a content of more than 83% of the pure title compound, in addition to 8-18% of isomeric methyl 2-amino-benzothiazole-5-carboxylate. Suspension in and brief heating at 70° C. with ethyl acetate, cooling to 30° C. and filtration give the pure title compound of melting point >250° C. If the reaction is carried out in acetic acid (instead of in chlorobenzene), the content of the undesired isomeric methyl 2-amino-benzothiazole-5-carboxylate is only about 5%.
Reaction SMILES: [C:1]([C@@H:5]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]=[N+]=[N-])[CH:13]=1)[CH2:6][CH2:7][S:8][CH3:9])([O:3][CH3:4])=[O:2].[H][H]>CO.[Pd]>[C:1]([C@@H:5]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=1)[CH2:6][CH2:7][S:8][CH3:9])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1cccc(CN=[N+]=[N-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)c1cccc(CN)c1

Procedure:
To a solution of the product from Step B (11.8 g, 35.08 mmol) in 150 mL of methanol under nitrogen was added 1.5 g 10% palladium on carbon. Hydrogen was applied to the mixture at 1 atmosphere for 1.5 h. The reaction mixture was filtered and concentrated in vacuo to obtain 10.3 g (34.76 mmol) of crude product as an oil. The crude product was chromatographed on 500 g of silica gel with chloroform/methanol 95/5 as eluant to afford the title compound as an oil. 1HNMR (300 MHz, CDCl3)δ7.78 (1H, s), 7.68 (1H, d, J=7 Hz), 7.47 (1H, d, J=7 Hz), 7.40 (1H, t, J=8 Hz), 7.02 (1H, d, J=7 Hz), 4.93 (1H, q, J=5 Hz), 3.92 (2H, s), 3.79 (3H, s), 2.59 (2H, t, J=8 Hz), 2.24 (1H, m), 2.12 (1H, m), 2.10 (3H, s), 1.85 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:16]1[CH:17]=[CH:18][N:19]=[C:20]2[C:25]=1[N:24]=[CH:23][C:22]([O:26][CH3:27])=[CH:21]2>CN(C=O)C>[CH3:27][O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[CH:17][CH:18]=[N:19]2)=[N:24][CH:23]=1
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cnc2c(Oc3ccc(N)cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Alternatively, the title compound may be prepared by the following method: In a nitrogen purged sealed pressure vessel, dissolved 4-aminophenol (0.617 g, 5.65 mmol) in DMF (0.030 L). Cesium carbonate (3.68 g, 11.3 mmol) was added and the mixture was stirred at RT for 5 min. Added 8-chloro-3-methoxy-1,5-naphthyridine (1.00 g, 5.14 mmol), heated to 90° C., stirred for 17 h. The mixture was allowed to cool to RT and was concentrated. The crude material was triturated with methanol, filtered, washed with methanol followed by water, and air dried to yield 4-(7-methoxy-1,5-naphthyridin-4-yloxy)benzenamine as brown solid. MS [M+H]=268.1; Calc'd 267.3 for C15H13N3O2.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>CN(C)C=O>[S:18]1[CH:19]=[CH:20][C:16]([CH2:15][O:14][C:12]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:3][CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[CH:13]=2)=[CH:17]1
Reactant: COC(=O)c1ccc(OCc2ccsc2)cc1O
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccsc2)cc1OCOCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred suspension of sodium hydride (1.53 g; 60% w/v dispersion in mineral oil; 38.3 mmol) in dimethylformamide (100 mL) is treated, portionwise, with methyl 2-hydroxy-4-(3-thienylmethoxy)benzoate (8.44 g) and stirred for 40 minutes. The mixture is treated with 2-(trimethyl-silyl)ethoxymethyl chloride (6.39 g), in one portion, and stirred at ambient temperature for three hours. It is then evaporated to dryness and the resulting residue is partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer is washed with brine (150 mL), dried over magnesium sulphate, filtered and concentrated in vacuo, to give methyl 4-(3-thienylmethoxy)-2-(2-trimethylsilylethoxy)methoxybenzoate, in the form of a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][CH2:4][NH:3]1.[CH3:15]I>>[CH3:15][N:3]1[CH2:4][CH2:5][C@H:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: CI
Product: CN1CC[C@H](NC(=O)OC(C)(C)C)C1=O

Procedure:
(S)-tert-butyl 1-methyl-2-oxopyrrolidin-3-ylcarbamate was prepared from compound (S)-tert-butyl 2-oxopyrrolidin-3-ylcarbamate (Example 6) and methyl iodide according to the general procedure of Example 9. The crude product was purified by column chromatography, eluting with 25% acetone/hexanes to provide compound (2a) in 45% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[F:9].[C:10]([Si](C)(C)C)#[CH:11].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:10]#[CH:11])[C:3]=1[F:9]
Reactant: C#C[Si](C)(C)C
Reactant: Fc1c(Cl)cccc1I
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: C#Cc1cccc(Cl)c1F
Yield: 82.9 %

Procedure:
The title compound was prepared according to the procedure described in step-5 and step-6 of Intermediate-2 by using 1-chloro-2-fluoro-3-iodobenzene (1.0 g, 3.9 mmol), ethynyl(trimethyl)silane (0.541 g, 5.5 mmol), copper iodide (0.027 g, 0.14 mmol), bis(triphenylphosphine) palladium(II) chloride (0.050 g, 0.072 mmol), TBAF (catalytic) and DCM to afford 0.500 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 4.66 (s, 1H), 7.25 (t, J=8.4 Hz, 1H), 7.54 (t, J=7.2 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H).
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[C:13](=[O:15])[CH3:14]>>[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[C:13]([OH:15])([CH3:1])[CH3:14]
Reactant: CC(=O)c1c(C)cc(C)cc1C
Reactant: C[Mg]Cl
Product: Cc1cc(C)c(C(C)(C)O)c(C)c1

Procedure:
According to Example 2, MeMgCl (2.9 M; 0.76 mL, 2.2 mmol, 1.10 equiv) was reacted with 1-(2,4,6-trimethyl-phenyl)-ethanone (324 mg, 2.00 mmol) in the presence of LaCl3.2LiCl (0.33 M; 6.06 mL, 2.00 mmol, 1.00 equiv). Column chromatographical purification (silica; pentane:Et2O 9:1) afforded the desired product as colorless, crystalline solid, mp=106−107° C. (217 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[O:26][CH2:25][CH2:24][N:23]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[O:26][CH2:25][CH2:24][N:23]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCN(CCC(=O)O)C4)no2)cc1Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 47.9 %

Procedure:
Ethyl 3-[9-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]propanoate (Preparation 88) (60 mg, 0.123 mmol) was dissolved in ethanol (5 ml). 2M sodium hydroxide (0.309 ml, 0.617 mmol) was added and the reaction mixture was stirred at 60° C. for 4 h. The solvent was evaporated then the reaction mixture was diluted with water and neutralised with 2M hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to give the product as a colourless solid (27 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2=[O:12].[CH3:13][N:14](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.[C-]#N.[C-]#N.[Zn+2]>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:13]#[N:14])=[CH:10][CH:9]=2)[C:5](=[O:12])[NH:6]1
Reactant: CN(C)C=O
Reactant: O=C1NC(=O)c2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)C(=O)NC2=O
Temperature: 200 °C
Yield: 27.4 %

Procedure:
A mixture of 5-bromoisoindoline-1,3-dione (2.5 g, 11.06 mmol) and Pd(Ph3P)4 (1.406 g, 1.217 mmol) in DMF (50 ml) was accurately degassed with nitrogen, then Zn(CN)2 (1.299 g, 11.06 mmol) was added, and the solution, splitted in 5 vials, was heated under microwave irradiation at 200° C. for 1 hour. A 3% aqueous solution of NH4OH (200 ml) was added, and the organic phase was extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with brine (150 ml), dried over sodium sulfate and concentrated to dryness. The crude was purified by silica gel flash chromatography (100% DCM to DCM:MeOH=99:1) to afford 1,3-dioxoisoindoline-5-carbonitrile as (0.522 g, 3.03 mmol, 27.4% yield, MS/ESI+ 172.9 [MH]+).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][NH:5][C:6](=[O:14])[CH:7]([CH2:12][SH:13])[CH2:8][CH:9]([CH3:11])[CH3:10]>O.Cl>[SH:13][CH2:12][CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([NH:5][CH2:4][CH:3]=[O:2])=[O:14]
Reactant: COC(CNC(=O)C(CS)CC(C)C)OC
Agent: Cl
Solvent: O
Product: CC(C)CC(CS)C(=O)NCC=O
Reaction time: 1 h

Procedure:
The N-(2,2-dimethoxyethyl)-2-(mercaptomethyl)-4-methylpentanamide obtained in Example 2 is dissolved in 10 ml of water and treated with a few drops of 10% hydrochloric acid. After standing for 1 hour at 25° C., the water is removed in vacuo and the product is obtained as a powder by triturating with acetonitrile.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:13]([CH3:37])([CH3:36])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:31][CH2:32][C:33](=[O:35])[CH3:34])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:40][Mg]Br.Cl>O1CCCC1.C(OCC)C>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C:13]([CH3:36])([CH3:37])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:31][CH2:32][C:33]([OH:35])([CH3:40])[CH3:34])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(=O)CNc1cc(-c2ccccc2Cl)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(NCC(C)(C)O)cc1-c1ccccc1Cl
Temperature: 65 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of 100 mg (0.175 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-oxo-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide in 1 ml tetrahydrofuran was added a 3 N solution of methylmagnesium bromide in diethyl ether at room temperature. The reaction mixture was stirred at room temperature for 1 h and at 65° C. for 3 h. After cooling to room temperature few drops of a 1 N aqueous solution of hydrochloric acid were added to the reaction mixture, followed by extraction with dichloromethane and washing with saturated sodium carbonate solution. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 51 mg (50%) of the title compound as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][C:13](=[O:30])[C:14]=2[C:15]2[CH:20]=[C:19]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:18]=[CH:17][C:16]=2[CH:28]=[CH2:29])[N:10]=1>CCOC(C)=O>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][C:13](=[O:30])[C:14]=2[C:15]2[CH:20]=[C:19]([C:21]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[O:22])[CH:18]=[CH:17][C:16]=2[CH2:28][CH3:29])[N:10]=1
Reactant: C=Cc1ccc(C(=O)N2CCCC2)cc1-c1c(=O)ccn2nc(Oc3ccc(F)cc3F)ccc12
Solvent: CCOC(C)=O
Product: CCc1ccc(C(=O)N2CCCC2)cc1-c1c(=O)ccn2nc(Oc3ccc(F)cc3F)ccc12
Reaction time: 0.5 h

Procedure:
2-(2,4-difluorophenoxy)-5-[5-(pyrrolidin-1-ylcarbonyl)-2-vinylphenyl]-6H-pyrido[1,2-b]pyridazin-6-one (14 mg, 0.03 mmol) was disolved in EtOAc (2 mL) and purged with nitrogen (3×). A catalytic amount of activated Pd on carbon was added and the system was purged with nitrogen (3×) and hydrogen (3×). The reaction was complete in 30 min and the reaction was filtered through celite and concentrated. The crude residue was purified via silica gel chromatography (EtOAc/CH2Cl2/MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:56][O:57][CH2:58][CH2:59][CH2:60][NH2:61]>CN(C=O)C>[CH3:56][O:57][CH2:58][CH2:59][CH2:60][NH:61][C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:32]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: COCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCCCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c1C
Temperature: 25 °C
Reaction time: 240 h

Procedure:
To a mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.19 mmol), HOBt (31 mg, 1.2 eq.), EDAC.HCl (44 mg, 1.2 eq.) and 3-methoxy-propylamine (42 mg, 1.1 eq.) in DMF (2 mL) was added TEA (0.066 mL, 2.5 eq.). After stirring at rt for 10 days, the reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, concentrated and purified on a silica gel column to give the titled compound as a pale orange waxy solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[Cl:8][C:4]1[N:3]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[N:14]=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=[N:17]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(Cl)n1
Reactant: C#CCCn1nc2ccccc2n1
Product: Clc1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 5.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 2,6-dichloropyridine (150 mg, 1.01 mmol) and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (0.17 g, 1.00 mmol, Example 109(D)). Microwave conditions: 120° C. for 15 min The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 15 mg (53 μmol, 5%) of 2-(4-(6-chloropyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.