Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:9]1[CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
30 g of benzyl bromide are added dropwise to a mixture of 25 g of ethyl isonipecotate and 25 g of K2CO3 in 125 ml of DMF, while maintaining the temperature of the reaction mixture between 25 and 30° C., and the resulting mixture is then stirred at RT for 1 hour. The reaction mixture is poured onto 1 liter of ice-cold water and extracted twice with ether, the organic phase is washed with water and dried over MgSO4, and the solvent is evaporated off under vacuum. The resulting oil obtained is distilled off under reduced pressure. 29.2 g of the expected product are obtained; b.p.=120-122° C. at 2.7 Pa.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[CH:19][C:20](O)=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[C:17]([Cl:16])[CH:18]=[CH:19][C:20]=1[O:13][C@H:10]1[CH2:9][CH2:8][C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:15])[CH3:14])[CH2:12][CH2:11]1
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)ccc1O[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1

Procedure:
In a manner similar to the method described in example 94b, cis-4-(tert-buyl-dimethyl-silanyloxy)-cyclohexanol (2.7 g, 12 mmol) was reacted with methyl 5-chloro-2-hydroxybenzoate (1.77 g, 9.5 mmol) and diisopropyl azodicarboxylate, triphenylphosphine in tetrahydrofuran to give trans-2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-benzoic acid methyl ester as a yellow oil (Yield 2.7 g, 71%).
Reaction SMILES: [C:1]([C:4]1[N:13]=[C:12]2[C:7]([C:8]([C:14]3[CH:15]=[CH:16][C:17]([F:28])=[C:18]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:19]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:29][Mg]Br.[NH4+].[Cl-]>C1COCC1>[F:28][C:17]1[CH:16]=[CH:15][C:14]([C:8]2[C:7]3[C:12](=[N:13][C:4]([C:1]([OH:3])([CH3:29])[CH3:2])=[CH:5][CH:6]=3)[N:11]=[CH:10][CH:9]=2)=[CH:19][C:18]=1[C:20]1[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc2c(-c3ccc(F)c(-c4ccccc4C#N)c3)ccnc2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(-c3ccc(F)c(-c4ccccc4C#N)c3)ccnc2n1
Temperature: -78 °C
Reaction time: 1.42 h
Yield: 69.1 %

Procedure:
To a stirred solution of 5′-[7-acetyl-[1,8]naphthyridin-4-yl]-2′-fluorobiphenyl-2-carbonitrile (from Example 58) (28.6 mg, 0.0778 mmol) in anhydrous THF (2 mL), cooled under nitrogen to −78° C., was added dropwise methylmagnesium bromide (3.0 M solution in Et2O, 26.0 μL, 0.078 mmol). The mixture was stirred at −78° C. for a total of 85 min, adding more methylmagnesium bromide (3.0 M solution in Et2O, 26.0 μL, 0.078 mmol) after 45 min and 70 min. Saturated aqueous NH4Cl (2 mL) was then added and the mixture was allowed to warm to room temperature. The mixture was partitioned between ethyl acetate (15 mL) and water (10 mL). The aqueous layer was extracted further with ethyl acetate (15 mL), and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 3% MeOH/CH2Cl2, to afford 20.6 mg (69%) of the title compound as a white solid. δH (360 MHz, CDCl3) 1.67 (6H, s), 5.32 (1H, s), 7.44 (1H, t, J 9.1), 7.51 (1H, d, J 4.6), 7.54 (1H, td, J 7.7, 1.1), 7.58-7.65 (4H, m), 7.71 (1H, td, J 7.7, 1.1), 7.84 (1H, dd, J 7.7, 1.1), 8.51 (1H, d, J 8.8), 9.15 (1H, d, J 4.2). m/z (ES+) 384 [MH]+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:11]([NH2:21])=[CH:10][C:9]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH3:38])[CH:30]=2)[CH:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:6][O:7][C:8]1[C:9]([NH:22][C:23]2[N:28]=[C:27]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]([CH3:38])[CH:30]=3)[CH:26]=[CH:25][N:24]=2)=[CH:10][C:11]([NH:21][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:13]=1
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 17.3 %

Procedure:
A solution of acryloyl chloride (58.4 mg, 0.64 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of 4-methoxy-N′-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 110, 286 mg, 0.64 mmol) and DIPEA (0.134 mL, 0.77 mmol) in CH2Cl2 (20 mL), which was cooled in an ice/water bath. The mixture was stirred for 1.5 h at 0° C. More DIPEA was added (30 μL) then more acryloyl chloride (20 mg) was added dropwise as a solution in CH2Cl2 (1 mL). This mixture was stirred for 2 h and then diluted with CH2Cl2 (50 mL). This solution was washed with sat. NaHCO3 solution (2×25 mL) and then the combined aqueous washes were extracted with CH2Cl2 (2×25 mL). The combined organic solutions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting gum was triturated with diethyl ether to give a solid which was collected by filtration and dried in vacuo. Purification by FCC, eluting with 0-8% 7N methanolic ammonia in CH2Cl2 gave the title compound (55 mg, 17%) as a light grey solid after trituration with diethyl ether (with a few drops of CH3OH); 1H NMR: 2.27 (3H, s), 2.53-2.59 (4H, m), 2.85-2.91 (4H, m), 3.87 (3H, s), 3.91 (3H, s), 5.75 (1H, d), 6.24 (1H, d), 6.67 (1H, dd), 6.89 (1H, s), 7.15-7.28 (3H, m), 7.53 (1H, d), 7.89 (1H, s), 8.28 (1H, d), 8.32 (1H, d), 8.58 (1H, s), 8.81 (1H, s), 9.07 (1H, s); m/z: ES+ MH+ 498.58.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH2:17]>CCOC(C)=O>[C:4]([O:3][C:1]([N:8]1[C:13](=[O:17])[CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A solution of NaIO4 (5.6 g, 26 mmol) in water (30 mL) and RuCl3 (14 mg) were added to a solution of Boc-(R)-piperidine-3-carboxylic acid (1.5 g, 6.6 mmol) in EtOAc (30 mL). The reaction mixture was stirred overnight at ambient temperature. The two layers were separated and the aqueous phase was extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL×3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH=20:1) to afford (S)-1-(tert-butoxycarbonyl)-6-oxopiperidine-3-carboxylic acid (790 mg, 49% yield) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:34])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]2=[C:10]([Br:34])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1cccc(OC)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1cccc(OC)c1

Procedure:
Prepared in analogy to that of Example 103(a) from 2,3-dibromo-1-(3-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, NBS and BzOOBz in carbontetrachloride. The title compound, ESI MS (m/z): 561 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[C:6]([O:21][CH3:22])[CH:5]=1)(=[O:3])[CH3:2].[C:23]([C:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1)#[CH:24]>C(Cl)Cl>[C:25]1([C:23]#[C:24][C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]=2[O:21][CH3:22])[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: COc1cc(C(C)=O)ccc1OS(=O)(=O)c1ccc(C)cc1
Reactant: C#CC1=CCCCC1
Solvent: ClCCl
Product: COc1cc(C(C)=O)ccc1C#CC1=CCCCC1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-acetyl-2-methoxy-phenyl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: DCM; yield (114 mg, 90%); 1H NMR δ (CDCl3): 7.53-7.41 (m, 3H), 6.29 (m, 1H), 3.92 (s, 3H), 2.51 (s, 3H), 2.31-2.12 (dm, 4H), 1.73-1.57 (m, 4H); LCMS m/z: 254.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N-:12]=[N+:13]=[N-:14].[Na+].O>CN(C=O)C>[N:12]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)=[N+:13]=[N-:14]
Reactant: Clc1nccc2ncccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1nccc2ncccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of 5-chloro-1,6-naphthyridine (3.3 g, 20.1 mmol) in DMF (40 mL) was added sodium azide (6.0 g, 88.5 mmol). The mixture was stirred at 80° C. overnight. The mixture was poured into water (120 mL). The aqueous phase was extracted with EtOAc (150 mL×4). The combined organic layers were washed with brine (100 mL×3), dried over sodium sulfate, and concentrated under reduced pressure to give 3.4 g of the crude product as a brown solid. MS (ESI): m/z 172 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C:7](=[N:11][OH:12])[C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:18])(=O)=O>O.CO>[C:1]([O:5][C:6](=[O:13])[C:7](=[N:11][O:12][CH3:18])[C:8]([CH3:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Reactant: COS(=O)(=O)OC
Solvent: CO
Solvent: O
Product: CON=C(C(C)=O)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of 215 g of Na2CO2 in 2200 ml of water is added at room temperature a solution of 128 g of 2-hydroxyiminoacetoacetic acid-tert.butyl ester in 475 ml of methanol. 255 g of dimethyl sulphate are added, dropwise, at 8°-10°, and after 3 hours at 8°-10° and 15 hours at room temperature, the mixture is filtered. The filtrate is extracted 3 times with ethyl acetate extracted 3 times with ethyl acetate, dried over magnesium sulphate and evaporated to obtain the heading compound.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=2)[C:22]1=[O:34])(=O)C.Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:49]=[CH:48][N:47]([CH2:50][CH3:51])[N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1>>[C:30]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:34])[N:21]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:36]3[CH:37]=[C:38]([NH:44][C:45]4[CH:49]=[CH:48][N:47]([CH2:50][CH3:51])[N:46]=4)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=3)[C:6]=1[CH2:5][OH:4])[CH2:29]2)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Reactant: CCn1ccc(Nc2cc(Br)cn(C)c2=O)n1
Product: CCn1ccc(Nc2cc(-c3cccc(N4Cc5cc(C(C)(C)C)ccc5C4=O)c3CO)cn(C)c2=O)n1

Procedure:
Following the same general procedure as described for 105, reaction of 103f (556 mg, 1.20 mmol) with 106a (300 mg, 1.00 mmol) gave a 20% (101 mg) yield of 106 as a white solid: mp 175-177° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 8.01 (d, 1H, J=2.0 Hz), 7.73 (d, 1H, J=7.5 Hz), 7.71 (s, 1H), 7.62 (dd, 1H, J=8.0, 1.0 Hz), 7.52 (d, 1H, J=2.5 Hz), 7.49 (t, 1H, J=7.5 Hz), 7.42 (dd, 1H, J=7.5, 1.0 Hz), 7.36 (dd, 1H, J=7.5, 1.0 Hz), 7.25 (d, 1H, J=2.0 Hz), 6.06 (d, 1H, J=2.0 Hz), 4.94 (s, 2H), 4.89 (t, 1H, J=5.0 Hz), 4.35 (d, 2H, J=5.0 Hz), 3.98 (q, 2H, J=7.5 Hz), 3.58 (s, 3H), 1.37 (s, 9H), 1.31 (t, 3H, J=7.5 Hz); MS (ESI+) m/z 512.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][C:13]=1[NH2:21]>>[NH2:21][C:13]1[CH:14]=[C:15]([C:16]2[O:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:19]=[CH:20][C:12]=1[O:11][CH3:10]
Reactant: Cc1ccc(N)c(O)c1
Reactant: COc1ccc(C(=O)O)cc1N
Product: COc1ccc(-c2nc3ccc(C)cc3o2)cc1N

Procedure:
Prepared by the method of Example 1a), from 2-amino-5-methylphenol (368 mg, 2.9 mmol) and 4-methoxy-3-aminobenzoic acid (500 mg, 2.9 mmol) the subtitle compound was obtained, 75 mg (10%). 1H NMR (CDCl3) δ 7.69–7.58(m, 4H), 7.35(bs, 1H), 6.92(d, J=7.9 Hz), 3.85(s, 3H), 2.51(s, 3H). MS 255 m/z (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[C:6]1([CH:12]2[C:15]3([CH2:17][O:16]3)[O:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[OH:16][CH2:17][C:15]1([N:2]2[N:3]=[N:4][CH:5]=[N:1]2)[CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:13][O:14]1
Reactant: c1ccc(C2COC23CO3)cc1
Reactant: c1nnn[nH]1
Solvent: C1CCOC1
Product: OCC1(n2ncnn2)OCC1c1ccccc1
Reaction time: 1 h
Yield: 41.2 %

Procedure:
1H-Tetrazole (0.078 g, 1.1 mmol) in dry THF (2 mL) was added dropwise to a stirred solution under N2 of 3-phenyl-1,5-dioxaspiro[3.2]hexane (0.15 g, 0.94 mmol) in dry THF (2 mL) at 0° C. The reaction mixture was stirred for 1 hour and then concentrated. The resultant yellow oil was purified by flash chromatography on silica gel (CH2Cl2/methanol 100:0 to 98:2) to provide 2-hydroxymethyl-3-phenyl-2-(tetrazol-2-yl)oxetane as a pale yellow oil (0.090 g, 42%): IR (CDCl3) 3436 (br), 2916, 1319, 1054, 953 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 7.42 (m, 5H), 5.37 (dd, J=8.6, 6.9 Hz, 1H), 5.16 (dd, J=8.6, 6.1 Hz, 1H), 5.08 (dd, J=6.2, 6.2 Hz, 1H), 4.21 (dd, J=13.5, 7.5 Hz, 1H), 4.17 (dd, J=13.5, 7.4 Hz, 1H), 1.86 (dd, J=7.4, 7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 153.1, 133.2, 129.1, 128.5, 128.1, 100.9, 69.6, 62.6, 47.8; MS (EI) m/z 204 (M+—N2), 185, 173, 104 (100), 91, 78; Anal. calculated for C11H12N4O2: C, 56.89; H, 5.21; N, 24.12. Found: C, 56.76; H, 5.14; N, 23.78.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:13])[C:10](Cl)=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]1[CH2:26][NH:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=1>ClCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]1[CH2:26][N:25]([C:10]([N:9]([CH3:13])[CH3:8])=[O:11])[CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=1
Reactant: CN(C)C(=O)Cl
Reactant: Fc1ccc(Cl)c(C2=CC(c3ccccc3)NC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2Cl)=CC1c1ccccc1
Reaction time: 2 h

Procedure:
Triethylamine (0.600 mL, 4.28 mmol, 5.00 equiv) and dimethylcarbamoyl chloride (0.080 mL, 0.86 mmol, 1.00 equiv) were added to a solution of 4-(2-chloro-5-fluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (1-5, TFA salt, 0.856 mmol, 1 equiv) in dichloromethane (50 mL) at 23° C., and the resulting mixture was stirred for 2 h, then concentrated. The residue was partitioned between saturated aqueous sodium bicarbonate solution (75 mL) and ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was suspended in ethyl ether (2 mL) and the precipitate filtered to provide 4-(2-chloro-5-fluorophenyl)-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (1-6) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.40-7.30 (m, 5H), 7.26 (m, 1H), 7.03 (dd, 1H, J=9.0,2.9 Hz), 6.97.(m, 1H), 6.24 (m, 1H), 6.15 (m, 1H), 4.86 (ddd, 1H, J=13.9, 5.6, 2.2 Hz), 4.49 (dt, 1H, J=13.9, 2.0 Hz), 2.86 (s, 6H). LRMS m/z (M+H) 345.0 found, 345.1 required.
Reaction SMILES: [Mg].BrCCBr.Cl[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15].[CH2:16]([N:23]1[CH2:28][CH2:27][O:26][CH:25]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[CH2:16]([N:23]1[CH2:28][CH2:27][O:26][CH:25]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([OH:30])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: COc1ccccc1CCl
Agent: [Mg]
Solvent: BrCCBr
Solvent: CCOCC
Product: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 122 %

Procedure:
Solid magnesium turnings (9.5 g, 28 equiv.) under nitrogen atmosphere at room temperature were stirred vigorously with a magnetic stirring bar overnight. The magnesium was then covered with dry diethyl ether and to the suspension was added 1,2-dibromoethane (50 μL). A cold bath was then applied followed by dropwise addition of 1-chloromethyl-2-methoxy-benzene (18.18 g, 5 equiv. available from Aldrich Chemical Company) in diethyl ether (71 mL) which maintained the temperature at up to 15° C. The resulting black suspension was stirred at room temperature for 30 minutes and cooled down at −20° C. A solution of (4-Benzyl-morpholin-2-yl)-phenyl-methanone (4 g, 1 equiv.) in diethyl ether (50 mL) was then added dropwise via canula. The reaction mixture was left to warm to room temperature over two hours and then quenched by addition of aqueous saturated solution of NaHCO3 (50 mL). The aqueous solution was extracted with diethyl ether, the organic phase dried with MgSO4, evaporated in vacuo to give 7 g of a yellow amorphous solid. The compound was taken without further purification in the next step. FIA [M+H]+=404.
Reaction SMILES: [C:1]([OH:24])(=O)[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[NH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].CCN=C=NCCCN(C)C>CC#N>[C:1]([NH:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])(=[O:24])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (1 mmol) was taken up in CH3CN (5 mL) along with tert-butyl 2-aminoethylcarbamate (1 mmol) and EDCI (1.1 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. It was then washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (CH2Cl2) afforded tert-butyl 2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylcarbamate.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[N:23]=[C:24]([NH:27][C:28](=[O:30])[CH3:29])[S:25][CH:26]=2)=[CH:16][C:15]=1[F:31])=[O:11])[NH:2]C(OC(C)(C)C)=O.O1CCOCC1.[ClH:38]>ClCCl>[ClH:38].[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[N:23]=[C:24]([NH:27][C:28](=[O:30])[CH3:29])[S:25][CH:26]=2)=[CH:16][C:15]=1[F:31])=[O:11])[NH2:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(COC(=O)NNC(=O)OC(C)(C)C)c(F)c2)cs1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(CCc2ccc(COC(=O)NN)c(F)c2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}-2-fluorobenzyl tert-butyl hydrazine-1,2-dicarboxylate (147.0 mg, 0.325 mmol) in anhydrous dichloromethane (2 ml) was added 4M hydrogen chloride dioxane solution (2 ml). After stirring at room temperature for 2 hr, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. This operation was performed 3 times to remove hydrogen chloride gas azeotropically. The residue was suspended in a mixture of ethanol (2 ml) and ethyl acetate (8 ml) and filtered. The filtered product was washed twice with ethyl acetate, and dried under reduced pressure to give 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}-2-fluorobenzyl hydrazinecarboxylate hydrochloride (129.1 mg, quantitative) as a white solid.
Reaction SMILES: N1C2C(=NC=CC=2)N([O:10][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=O)N=1.[CH:43]1([CH2:46][NH2:47])[CH2:45][CH2:44]1>CC(N(C)C)=O>[CH:43]1([CH2:46][NH:47][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=3[Cl:39])(=[O:30])=[O:31])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:10])[CH2:45][CH2:44]1
Reactant: NCC1CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCC1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added C-cyclopropyl-methylamine (23 mg, 2 eq.). The mixture was stirred at rt for 18 hours. The reaction was concentrated, diluted with DCM, washed with sat.NaHCO3 and water, concentrated and triturated with methanol to give the titled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13]O.S(Cl)([Cl:17])=O>C1COCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:17][CH2:13][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:7][C:2]=1[F:1]
Reactant: OCc1ccc(-n2cccn2)cc1F
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(-n2cccn2)ccc1CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2-fluoro-4-(1H-pyrazol-1-yl)phenyl)methanol (0.71 g) in THF (15.0 mL) was added thionyl chloride (0.40 mL) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, saturated aqueous sodium bicarbonate was added thereto, and the mixture was partitioned. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.50 g).