Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4](OCC)[C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][CH:6]=1)C.Cl.[NH2:30][OH:31]>C1COCC1.O.C(Cl)Cl.[Cl-].[Na+].O>[OH:31][N:30]=[CH:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][CH:6]=1
Reactant: NO
Reactant: CCOC(OCC)c1ccc(CN(C(=O)OC(C)(C)C)C2CCOCC2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccc(C=NO)cc1)C1CCOCC1
Temperature: 22.5 °C
Reaction time: 18 h
Yield: 70.5 %

Procedure:
A solution of tert-butyl 4-(diethoxymethyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate (A-3) (2.80 kg, 7.12 mol) in THF (28.0 L) and water (2.80 L) is stirred at about 20° C. Hydroxylamine hydrochloride (593 g, 8.54 mol) is added while maintaining the reaction temperature between 20-25° C. The reaction mixture is stirred at about 20° C. for 16-20 h then diluted with CH2Cl2 (8.4 L) and 50% brine (11.2 L) and stirred for at least 5 min. The phases are separated then the organic phase is washed with 50% brine (2×2.8 L), dried (Na2SO4) and concentrated. The concentrate is diluted with MeOH (1.4 L) and re-concentrated. The concentrate is diluted with MeOH (14.0 L) and transferred to a reaction vessel. The solution is warmed to about 25° C. then water (14.0 L) is added over about 1-1.5 h; after about 10 L of water is added, the mixture is seeded and a hazy suspension is observed. Additional water (8.4 L) is added over 1.5 h to further precipitate the product. After aging, the solid is collected by filtration. The filter-cake is washed with heptane (5.6 L) and dried to afford tert-butyl 4-((hydroxyimino)methyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate (A-4) (1678 g; 71%, 91.5 area % purity by HPLC) as an off-white powder. 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.24 (d, J=7.9 Hz, 2H), 4.40 (br s, 3H), 3.96 (dd, J=10.4, 3.6 Hz, 2H), 3.41 (br m, 2H), 1.69-1.61 (m, 4H), 1.39 (br s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].Br[CH2:10][C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][N:5]([CH2:10][C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:6]=1[CH3:7]
Reactant: CC(C)NC(=O)CBr
Reactant: Cc1n[nH]c(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nn(CC(=O)NC(C)C)c(C)c1Br
Temperature: 70 °C

Procedure:
To a 4 mL vial equipped with a magnetic stir bar were added 4-bromo-3,5-dimethyl-1H-pyrazole (50 mg, 0.286 mmol), 2-bromo-N-isopropylacetamide (51.4 mg, 0.286 mmol), K2CO3 (118 mg, 0.857 mmol), and acetonitrile (2 mL). The contents of the vial were stirred to give a white suspension. The vial was heated in a sand bath to 70° C. for 24 hours. The reaction mixture was subsequently partitioned between water (10 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous layer was back-extracted with ethyl acetate (15 mL). The combined organic layers were concentrated to give the title compound as a white solid, which was used without further purification (80 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH:28]([CH2:33][O:34][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH2:27]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:27][CH:28]1[CH2:33][O:34][Si:35]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:42]([CH3:44])[CH3:43]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](OCC1CN(Cc2nnc3ccc(F)cn23)CCN1C)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[Si](OCC1CN(Cc2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CCN1C)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Intermediate A (115.4 mg, 0.71 mmol) was added to a mixture of NaH (60% in mineral oil, 87.2 mg, 2.18 mmol) in DMF (4 mL) at RT and stirred for 15 min. Intermediate 56d (237 mg, 0.54 mmol) was then added and the resulting mixture heated to 60° C. for 2 h. After cooling, the reaction was quenched with sat. aq. NH4Cl solution. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO3 solution and brine, and concentrated in vacuo. The resulting residue was loaded onto an SCX-2 cartridge, washed with MeOH then eluted with 1M NH3 in MeOH; concentration in vacuo gave the title compound as a brown residue (91 mg, 29%). LCMS (Method 3): Rt 3.08 min, m/z 579 [MH+].
Reaction SMILES: N1C=CC=CC=1.[CH3:7][CH:8]([CH3:31])[CH:9]([NH:14][C:15]([C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=[O:16])[C:10]([O:12][CH3:13])=[O:11].[C:32]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([C:19]3[S:18][C:17]([C:15]([NH:14][CH:9]([CH:8]([CH3:31])[CH3:7])[C:10]([O:12][CH3:13])=[O:11])=[O:16])=[N:21][CH:20]=3)=[CH:23][CH:24]=2)=[O:41])=[CH:43][CH:44]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)c3ccc(C(C)(C)C)cc3)cc2)s1)C(C)C
Reaction time: 0.08 h

Procedure:
Pyridine (0.11 ml) was added to a solution of methyl 2-(5-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 2, 150 mg) in DCM (3 ml) and the reaction mixture was stirred for 5 minutes. 4-tert-butylbenzoyl chloride (0.125 ml) was then added and the reaction mixture was stirred for 1 h. The reaction mass was quenched with water. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to get dark brown solid which was purified by silica gel column chromatography (EtOAc:CHCl3, 2:8) to get off white solid. The solid was crystallized in CHCl3/pet ether to give the title compound. Yield: 160 mg (72%) white solid. 1HNMR (DMSO-d6, 300 MHz): δ 10.38 (s, 1H), 8.76 (d, 1H), 8.41 (s, 1H), 7.94 (d, 2H), 7.91 (d, 2H), 7.8 (d, 2H), 7.58 (d, 2H), 4.33 (m, 1H), 3.69 (s, 3H), 2.27 (m, 1H), 0.95 (d, 6H); MS (ES+): m/z 494 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[C@@H:7](C1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)CC(NN1[C@@H](CC2C=CC=CC=2)COC1(C)C)=O)([CH3:4])([CH3:3])[CH3:2].[CH3:44][C:45]([CH3:73])([CH3:72])[C@H:46]([NH:51][C:52](=[O:71])[CH2:53][C:54]1[O:58][C:57]([C:59]2[CH:64]=[CH:63][C:62]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:61][CH:60]=2)=[CH:56][CH:55]=1)[C:47](=[O:50])[NH:48][CH3:49].C([Li])CCC>>[C:1]([O:5][C:6](=[O:43])[CH2:7][CH:53]([C:54]1[O:58][C:57]([C:59]2[CH:60]=[CH:61][C:62]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:63][CH:64]=2)=[CH:56][CH:55]=1)[C:52]([NH:51][C@H:46]([C:47](=[O:50])[NH:48][CH3:49])[C:45]([CH3:73])([CH3:72])[CH3:44])=[O:71])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(=O)[C@@H](NC(=O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1)C(C)(C)C
Reactant: CC(C)(C)OC(=O)[C@H](CC(=O)NN1[C@@H](Cc2ccccc2)COC1(C)C)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Agent: [Li]CCCC
Product: CNC(=O)[C@@H](NC(=O)C(CC(=O)OC(C)(C)C)c1ccc(-c2ccc(-c3ccccc3)cc2)o1)C(C)(C)C
Yield: 7 %

Procedure:
According to the procedure described in Example 13 for the preparation of N-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2(R)-(biphenyl-4-yl-1H-pyrrol-3-yl)succinamic acid t-butyl ester, but N-(2,2-dimethyl-1(S)-(N-methylcarbamoyl)-propyl)-2-(2-biphenyl-4-yl-furan-5-yl)-acetamide was instead deprotonated with n-butyllithium (3.1 equiv) and alkylated to furnish 17 mg (7%) of N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3-(2-(biphenyl-4-yl)-furan-5-yl)succinamic acid t-butyl ester as an amorphous solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:27]=[CH:26][C:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([OH:24])[CH:23]=3)[N:15]=[N:14]2)=[CH:10][CH:9]=1.[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43]Br)[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]>O1CCCC1.CN(C)C=O>[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43][O:24][C:22]3[CH:23]=[C:18]([C:16]4[N:15]=[N:14][N:13]([CH2:12][C:11]5[CH:26]=[CH:27][C:8]([Cl:7])=[CH:9][CH:10]=5)[CH:17]=4)[CH:19]=[CH:20][C:21]=3[CH3:25])[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]
Reactant: Cc1ccc(-c2cn(Cc3ccc(Cl)cc3)nn2)cc1O
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4cn(Cc5ccc(Cl)cc5)nn4)ccc3C)csc12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A suspension of cesium carbonate (1.11 g, 3.41 mmol), 5-[1-(4-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-2-methyl-phenol (0.75 g, 2.50 mmol) (from Example 34 supra) in tetrahydrofuran-N,N-dimethylformamide (5:2, 23 mL) was heated at 70° C. for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.76 g, 2.27 mmol) (from Example 1 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The precipitate was filtered, washed with ethyl acetate and dried to give 4-chloro-3-{5-[1-(4-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.33 g, 26%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH2:5][CH2:4][O:3]1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=O.N1CCCCC1>C(O)C>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][N:6]3[CH2:5][CH2:4][O:3][C:2]3=[O:1])[CH:9]=2)[NH:13][C:12]1=[O:17]
Reactant: O=C1Cc2cc(CN3CCOC3=O)ccc2N1
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)c(C=C2C(=O)Nc3ccc(CN4CCOC4=O)cc32)[nH]1

Procedure:
A solution of 5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (4.3 mmoles), 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (5.17 mmoles) and piperidine (3 mmoles) in ethanol (30 ml) is heated at reflux for 24 hours. The solid formed is filtered off, washed with ethanol, with water and then with ethanol and dried in vacuo to yield the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:12]=NN(C)C=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:17][N:18]1C(B2OC(C)(C)C(C)(C)O2)=C[CH:20]=[N:19]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:19]([CH3:20])[N:18]=[CH:17][CH:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(-c2ccnn2C)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. ESI-MS (m/z): 217 [M+1]+.
Reaction SMILES: [CH2:1]([C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:39]([OH:45])[CH2:40][CH:41]([OH:44])[CH2:42]O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:19]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[O:44][CH:41]([CH2:40][CH2:39][OH:45])[CH2:42][O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCCC(O)CO
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(=O)CCCCCCCC/C=C\C/C=C\CCCCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1(CCCCCCCC/C=C\C/C=C\CCCCC)OCC(CCO)O1
Temperature: 25 °C

Procedure:
A mixture of dilinoleyl ketone (I, previously prepared as described in Example 1, 527 mg, 1.0 mmol), 1,3,4-butanetriol (technical grade, ca. 90%, 236 mg, 2 mmol) and pyridinium p-toluenesulfonate (50 mg, 0.2 mmol) in 50 mL of toluene was refluxed under nitrogen overnight with a Dean-Stark tube to remove water. The resulting mixture was cooled to room temperature. The organic phase was washed with water (2×30 mL), brine (50 mL), and dried over anhydrous Na2SO4. Evaporation of the solvent resulted in a yellowish oily residual (0.6 g). The crude product was purified by column chromatography on silica gel (230-400 mesh, 100 mL) with dichloromethane as eluent. This afforded 0.5 g of pure II as colourless oil. 1H NMR (400 MHz, CDCl3) δ: 5.25-5.48 (8H, m, 4×CH═CH), 4.18-4.22 (1H, m, OCH), 4.08 (1H, dd, OCH), 3.82 (2H, t, OCH2), 3.53 (1H, t, OCH), 2.78 (4H, t, 2×C═C—CH2—C═C), 2.06 (8H, q, 4× allylic CH2), 1.77-1.93 (2H, m, CH2), 1.52-1.68 (4H, m, 2×CH2), 1.22-1.45 (32H, m), 0.86-0.94 (6H, t, 2×CH3) ppm.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(N(CC)CC)C.[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CN=C1>CN(C=O)C.C(OCC)C>[I:1][C:2]1[N:3]=[CH:4][N:5]([C:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Ic1c[nH]cn1
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-iodoimidazole (50 g, 258 mmoles) in DMF (500 ml) was added triethyl amine (37.7 ml, 270.6 mmoles) and than triphenylmethyl chloride (69.7 g, 250 mmoles). After stirring at room temperature for 48 hours, the solution was poured into ice water (2.5 L). The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether (200 ml) was added to the crude compound and the solution was filtered to yield 4-iodo-1-trityl-]H-imidazole (104.1, 93%) as a white solid. MH+(437)
Reaction SMILES: Cl.[C:2]1(/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH:31]=[C:30]([C:35]([OH:37])=[O:36])[CH:29]=[CH:28]3)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](C2CCCCO2)[N:14]=[CH:13]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[OH-].[Li+]>O>[NH:15]1[C:16]2[C:12](=[CH:11][C:10](/[C:9](/[C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]=[C:30]([C:35]([OH:37])=[O:36])[CH:29]=[CH:28]4)=[C:8](/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)\[CH2:38][CH3:39])=[CH:18][CH:17]=2)[CH:13]=[N:14]1
Reactant: CC/C(=C(/c1ccc2cc(C(=O)O)ccc2c1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC/C(=C(/c1ccc2cc(C(=O)O)ccc2c1)c1ccc2[nH]ncc2c1)c1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Hydrochloric acid (1 mL, 2M in ethyl ether) was added to a solution of (E)-6-(2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)-2-naphthoic acid (190 mg, 0.38 mmol) and EtOH (5 mL). The reaction was heated at 70° C. for 30 min, concentrated, and then redissolved in THF:EtOH (1:1, 5 mL). Lithium hydroxide (90 mg, 3.8 mmol) in H2O was added. The reaction was stirred at room temperature for 2 h, acidified to pH 3 with 1.0 M aqueous HCl soln, and then extracted with EtOAc (×2). The organic layers were combined, washed with water then brine, dried over Na2SO4, and concentrated. The crude material was purified on a reversed phase C-18 column eluted with 70-90% acetonitrile in water in the presence of 0.1% TFA affording the title compound as a beige solid (42 mg, 26%). 1H NMR (DMSO-d6, 300 MHz): δ 13.08 (br, 2H), 8.39 (s, 1H), 8.09 (d, 1H), 7.82-7.65 (m, 4H), 7.53 (d, 1H), 7.44 (s, 1H), 7.21-7.06 (m, 7H), 2.49 (q, 2H), 0.93 (t, 3H); LCMS: 419 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.S(Cl)([Cl:21])=O>N1C=CC=CC=1.C(Cl)Cl>[Cl:21][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccccc1-c1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1-c1ccc(CCl)cc1
Reaction time: 16 h
Yield: 87.9 %

Procedure:
2.0 g (8.25 mmol) of methyl 2-(4'-hydroxymethylphenyl)benzoate was dissolved in 1.31 g of pyridine and methylene chloride (20 ml). 1.47 g (12.4 mmol) of thionyl chloride was dropwise added thereto at room temperature, followed by stirring as such for 16 hours and under reflux by heating for 5 hours. After the reaction liquid was cooled and concentrated, a saturated aqueous solution of sodium hydrogencarbonate was added thereto, followed by the extraction with methylene chloride. The organic phase was washed with water, dried and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 1.89 g of the title compound as an oil (yield 88%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[N+:6]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([O-:8])=[O:7].N1C=CC=CC=1>O1CCCC1>[N+:6]([C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:1](=[O:4])[CH2:2][CH3:3])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: CCC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
Propionyl chloride (25.0 g, 270 mmol) was added dropwise to a solution of 4-nitroaniline (24.9 g, 180 mmol) and pyridine (43.7 ml, 540 mmol) in tetrahydrofuran (500 ml) under ice-cooling, the mixture was stirred under ice-cooling for 2 hour, and the solvent was distilled off under reduced pressure. The residue was poured into ice-water, and 33.5 g (95.7%) of the desired product was collected by filtration as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[NH:13][C:14]([C:16]2C=NN3C=C[CH:22]=[N:21][C:20]=23)=[O:15])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:34][C@@H:35]1[CH2:37][O:36]1.[NH:38]1[CH2:41][CH2:40][CH2:39]1>CN(C)C=O>[N:38]1([CH2:34][C@H:35]([OH:36])[CH2:37][N:11]2[CH:10]=[C:9]([NH:13][C:14]([C:16]3[C:20]4[N:21]=[CH:22][N:13]=[CH:9][C:10]=4[NH:11][N:12]=3)=[O:15])[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:25][CH3:26])=[N:12]2)[CH2:41][CH2:40][CH2:39]1
Reactant: C1CNC1
Reactant: COc1ccc(Cl)cc1-c1[nH]ncc1NC(=O)c1cnn2cccnc12
Reactant: ClC[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(C[C@@H](O)CN2CCC2)cc1NC(=O)c1n[nH]c2cncnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a suspension of N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (60 mg, 0.16 mmol) and cesium carbonate (212 mg, 0.65 mmol) in N,N-Dimethylformamide (1 mL) was added (S)-2-(chloromethyl)oxirane (26.3 mg, 0.28 mmol). The reaction mixture was stirred for 8 hours at room temperature, at which time LCMS analysis showed complete consumption of starting material. Azetidine (44 uL, 0.65 mmol) was added and the reaction mixture was stirred for an additional 16 hours at room temperature. The reaction mixture was filtered and purified by reverse phase HPLC to afford the title compound as a white solid (7.8 mg). LCMS (ESI) m+H=482.2; 1H NMR (400 MHz, DMSO) δ 9.69 (s, 1H), 9.34 (dd, J=7.0, 1.6, 1H), 8.78 (dd, J=4.2, 1.6, 1H), 8.66 (s, 1H), 8.27 (s, 1H), 7.50 (dd, J=8.9, 2.7, 1H), 7.40 (d, J=2.7, 1H), 7.33-7.26 (m, 2H), 4.94 (d, J=5.4, 1H), 4.21 (dd, J=13.7, 3.8, 1H), 3.99 (dd, J=13.8, 7.8, 1H), 3.84 (s, 3H), 3.77 (s, 1H), 3.17 (t, J=6.9, 4H), 2.39 (qd, J=12.0, 5.9, 2H), 2.02-1.93 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH:22]=[CH2:23])=[CH:17][C:16]=3[O:24][CH3:25])[O:10]C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)N2CC(C[Cl:45])OC2)C=CC=CC=1.C1(OC)C=C(CC=C)C=C(C([O-])=O)C=1O.[Na+].Cl>>[ClH:45].[CH3:25][O:24][C:16]1[CH:17]=[C:18]([CH2:21][CH:22]=[CH2:23])[CH:19]=[CH:20][C:15]=1[O:14][CH2:13][CH:11]([OH:10])[CH2:12][NH:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C=CCc1ccc(OCC2CN(C(c3ccccc3)c3ccccc3)CO2)c(OC)c1
Reactant: ClCC1CN(C(c2ccccc2)c2ccccc2)CO1
Agent: C=CCc1cc(OC)c(O)c(C(=O)[O-])c1
Agent: Cl
Agent: [Na+]
Product: C=CCc1ccc(OCC(O)CNC(c2ccccc2)c2ccccc2)c(OC)c1

Procedure:
3-Diphenylmethyl-5-(2-methoxy-4-allyl-phenoxymethyl)oxazolidine from 3-diphenylmethyl-5-chloromethyl-oxazolidine and sodium eugenolate*; this produce is hydrolysed with alcoholic-aqueous hydrochloric acid to give 1-(2-methoxy-4-allyl-phenoxy)-2-hydroxy-3-diphenylmethylaminopropane hydrochloride with a melting point of 143°.
Reaction SMILES: S(Cl)(Cl)=O.C(C1C=CC(C(O)=O)=CC=1)CCCCCCC.C(C1C=CC(C(Cl)=O)=CC=1)CCCCCCC.[Cl:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][C:46]=1[O:47][C:48]1[C:57]2[C:52](=[CH:53][C:54]([O:60][CH3:61])=[C:55]([O:58][CH3:59])[CH:56]=2)[N:51]=[CH:50][CH:49]=1)[NH2:43].[CH2:62]([C:70]1[CH:75]=[CH:74][C:73]([C:76]([N:78]=[C:79]=[S:80])=[O:77])=[CH:72][CH:71]=1)[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69]>C1(C)C=CC=CC=1.C(O)C>[Cl:39][C:40]1[CH:41]=[C:42]([NH:43][C:79]([NH:78][C:76](=[O:77])[C:73]2[CH:74]=[CH:75][C:70]([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])=[CH:71][CH:72]=2)=[S:80])[CH:44]=[CH:45][C:46]=1[O:47][C:48]1[C:57]2[C:52](=[CH:53][C:54]([O:60][CH3:61])=[C:55]([O:58][CH3:59])[CH:56]=2)[N:51]=[CH:50][CH:49]=1
Reactant: CCCCCCCCc1ccc(C(=O)N=C=S)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: CCCCCCCCc1ccc(C(=O)Cl)cc1
Agent: CCCCCCCCc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCCCc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(Cl)c2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 4-octylbenzoic acid (40 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 4-octyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 4-octyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-octyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (53 mg, yield 58%).