Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.[C:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)#[N:17].[Cl-].[NH4+]>C(OCC)C>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[NH:17])=[C:3]([F:10])[CH:4]=1
Reactant: Fc1cc(Br)c(F)cc1Br
Reactant: N#Cc1ccncc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: N=C(c1ccncc1)c1cc(F)c(Br)cc1F
Reaction time: 0.33 h
Yield: 50.5 %

Procedure:
A stirred solution of 1,4-dibromo-2,5-difluorobenzene (2.72 g) in anhydrous diethylether (50 ml) under nitrogen was cooled to −78° C. in a dry-ice/acetone bath then treated with n-butyllithium (1.6M in hexanes, 7.2 ml). The reaction mixture was stirred for 20 min and a solution of 4-cyanopyridine (1.4 g) in diethylether (60 ml) was added dropwise. The resulting mixture was stirred for a further 20 min then treated with saturated aqueous ammonium chloride. The ether layer was separated, washed with brine, dried (sodium sulfate) and concentrated under vacuum. The crude product was purified on an SPE cartridge (silica) using a cyclohexane/ethyl acetate gradient as eluant to give the title compound as a colourless gum (1.50 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].O=C(C)C[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2>>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: CC(=O)COc1cccc2cccnc12
Reactant: O=C(CBr)c1ccccc1
Product: O=C(COc1cccc2cccnc12)c1ccccc1
Yield: 69 %

Procedure:
8-(2-Oxo-2-phenylethoxy)quinoline (8a) was prepared from 2-bromoacetophenone by the same procedure as 7a in 69% yield. mp: 124°-125° C.; 1H-NMR (CDCl3): δ5.65 (s, 2H, OCH2), 6.95-8.97 (m, 11H, Ar--H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH2:14]([O:21][CH2:22]Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>COCCOCCOC>[CH2:14]([O:21][CH2:22][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCOCc1ccccc1
Reactant: COC(=O)C(=O)c1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: COC(=O)C(=O)c1cccn1COCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.8 %

Procedure:
Methyl pyrrol-2-ylglyoxylate (306 mg) in diglyme was treated with sodium hydride (63mg) and stirred at room temperature for 3 hr. Benzyloxymethyl chloride (376mg) was added and the mixture stirred at room temperature for a further 3 hr. The suspension was filtered and the filtrate evaporated. The residue, in ether, was washed with sodium bicarbonate solution, water and dried. Evaporation gave the crude product as a brown oil (530mg). Purification by preparative thin-layer chromatography gave the title compound as a colourless oil (250 mg,46%); τ values (DMSO-d6) include 6.10 (--CH3), 4.20 (>N--CH2 --), 5.47 (--OCH2 --), 2.70 (--Ph).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](/[CH:16]=[CH:17]/[C:18]3[O:22][CH:21]=[CH:20][CH:19]=3)=O)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.Cl.[NH2:24][OH:25].[OH-].[Na+]>>[O:22]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:17]1[O:25][N:24]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[CH:9][CH:10]=2)[CH:16]=1
Reactant: O=C(/C=C/c1ccco1)c1ccc(Oc2ccccc2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(Oc2ccc(-c3cc(-c4ccco4)on3)cc2)cc1

Procedure:
To a mixture of 3-furan-2-yl-1-(4-phenoxy-phenyl)-propenone (0.4 g, 1.4 mmol) and hydroxylamine hydrochloride (0.14 g, 2.1 mmol), was added sodium hydroxide (0.11 g, 2.8 mmol). The reaction mixture was heated to reflux for 3 days. The mixture was then concentrated, and neutralized with diluted HCl. Ethyl acetate and water were added. The organic layer was separated and dried over sodium sulfate. The solvent was removed and the residue was purified by column chromatography (silica, eluted with 20% ethyl acetate/hexanes) to give the desired isoxazole in poor yield (10 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[N:8]=N/N2CCCC2)=[CH:4][CH:3]=1.[Li]C(CC)C.[CH3:20][C:21]([CH3:23])=[O:22]>CCOCC>[NH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:21]([OH:22])([CH3:23])[CH3:20])=[CH:7][CH:6]=1
Reactant: Brc1ccc(/N=N/N2CCCC2)cc1
Reactant: CC(C)=O
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(C)(O)c1ccc(N)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a −78° C. solution of compound 134 (1 g, 3.95 mmol) in ether (20 mL) was added sec-BuLi (1.4 M in hexanes, 0.62 g, 9.67 mmol). The resulting solution was stirred for 30 min at −78° C., followed by addition of acetone (0.91 g, 15.81 mmol) dropwise at −78° C. The reaction mixture was warmed to room temperature overnight. The reaction mixture was partitioned between water and ether and the layers were separated. The aqueous layer was re-extracted with ether. The ether layers were the combined and concentrated in vacuo to yield crude 135 (0.33 g, 55.9%) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH:11]([CH:22]([CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20]C)=[O:9].CNC>C(O)C>[CH3:43][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH:11]([CH:22]([CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:9]
Reactant: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CCC/C=C\CCCCC)OC(=O)CCCCCN(C)C
Agent: CNC
Solvent: CCO
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CC/C=C\CCCCC)OC(=O)CCCCCN(C)C

Procedure:
Using an analogous procedure to that described for the synthesis of (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-yl 6-(dimethylamino)hexanoate 11, (6Z,15Z)-11-((Z)-dec-4-enyl)henicosa-6,15-dien-10-yl 6-(dimethylamino)hexanoate 21 was obtained as a colorless oil (1.2 g, 92%) from 5.6 M dimethylamine in ethanol (15 mL). 1H NMR (400 MHz, CDCl3) δ 5.44-5.28 (m, 6H), 4.95-4.88 (m, 1H), 2.33-2.19 (m, 10H), 2.08-1.90 (m, 12H), 1.70-1.23 (m, 9H), 1.23-1.14 (m, 26H), 0.93-0.85 (m, 9H). Rf 0.15 (10% MeOH—CH2Cl2).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O:17][CH2:18][CH:19]1[O:24][CH:23](Br)[CH:22]([O:26]C(C)=O)[CH:21]([O:30]C(C)=O)[CH:20]1[O:34]C(C)=O)=O>CC(C)=O.[OH-].[K+]>[C@@H:23]1([O:13][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=2)[O:24][C@H:19]([CH2:18][OH:17])[C@H:20]([OH:34])[C@H:21]([OH:30])[C@H:22]1[OH:26]
Reactant: CC(=O)OCC1OC(Br)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: OC[C@H]1O[C@@H](Oc2ccc(-c3ccccc3)cc2)[C@H](O)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of p-phenylphenol (250 mg, 1.46 mmol) in acetone, 1 mL of 10N KOH was added followed by acetobromogalactose (1.8 g, 4.37 mmol). The reaction mixture was stirred overnight at room temperature. TLC analysis showed no starting material left. 10N KOH (1 mL) was added to complete deacetylation and the solution was again stirred overnight. After evaporation of acetone, the crude material was taken up in ethyl acetate and washed with 5×150 mL of water. Ethyl acetate was dried with MgSO4 and concentrated under reduced pressure to obtain a white solid which was further purified by column chromatography using 30% methanol/ethyl acetate; 1H NMR (CD3OD) δ3.56-3.91 (m, 6H), 4.89 (m, 1H), 7.15-7.57 (m,9H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][O:14][C:15]3=[O:18])=[CH:11][CH:10]=2)O1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]([C:30]2([C:33]3[CH:43]=[CH:42][C:36]4[O:37][C:38]([F:41])([F:40])[O:39][C:35]=4[CH:34]=3)[CH2:32][CH2:31]2)=[O:29])[CH:24]=[CH:23][C:22]=1[CH3:44].C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[F:41][C:38]1([F:40])[O:37][C:36]2[CH:42]=[CH:43][C:33]([C:30]3([C:28]([NH:27][C:25]4[CH:24]=[CH:23][C:22]([CH3:44])=[C:21]([C:9]5[CH:17]=[C:16]6[C:12](=[CH:11][CH:10]=5)[CH2:13][O:14][C:15]6=[O:18])[N:26]=4)=[O:29])[CH2:32][CH2:31]3)=[CH:34][C:35]=2[O:39]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: CC1(C)OB(c2ccc3c(c2)C(=O)OC3)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc2c(c1)C(=O)OC2
Temperature: 120 °C

Procedure:
6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one (39 mg, 0.15 mmol), N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (37 mg, 0.10 mmol) and Pd(PPh3)4 (6 mg, 0.005 mmol) were placed in a microwave vial. DME (1 mL) and saturated aq. Na2CO3 (100 μL) were added and the reaction vial was flushed with N2 and sealed. The reaction was heated in the microwave at 120° C. for 20 minutes before it was partitioned between ethyl acetate and H2O. The organic layer was filtered and concentrated. The residue was dissolved in DMSO and purified by reverse-phase HPLC to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(3-oxo-1,3-dihydroisobenzofuran-5-yl)pyridin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 464.1, found 465.3 (M+1)+. Retention time 1.96 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 7.94-7.86 (m, 3H), 7.76-7.73 (m, 2H), 7.56 (d, J=1.5 Hz, 1H), 7.41-7.33 (m, 2H), 5.47 (s, 2H), 2.26 (s, 3H), 1.53-1.50 (m, 2H), 1.19-1.16 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][CH2:5][CH2:4][C:3]1=[N:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(O)(=O)C.C([BH3-])#N.[Na+].Cl[O-].[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:16])[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)NN=C1CCCC1(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC1CCCC1(C)C
Temperature: 85 °C
Reaction time: 10 h
Yield: 51.7 %

Procedure:
To a solution of tert-butyl 2-(2,2-dimethylcyclopentylidene)hydrazinecarboxylate (4.6 g) and acetic acid (9.4 g) in THF (80 mL) was added sodium cyanoborohydride (5.1 g) at room temperature. The reaction mixture was stirred at 85° C. for 10 hr, aqueous sodium hypochlorite solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (2.4 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:35][N:36]1[C:44]2[C:39](=[CH:40][C:41]([NH2:45])=[CH:42][CH:43]=2)[C:38](C)=[CH:37]1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11]([NH:45][C:41]1[CH:40]=[C:39]2[C:44](=[CH:43][CH:42]=1)[N:36]([CH3:35])[CH:37]=[CH:38]2)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: Cc1cn(C)c2ccc(N)cc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(=O)Nc2ccc3c(ccn3C)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 95.3 %

Procedure:
2,4-Dibenzyloxy-5-isopropylbenzoic acid (5.64 g, 15.0 mmol, 1.00 equiv.) in 80 mL dichloromethane at room temperature was treated with oxalyl chloride (2.00 g, 15.75 mmol, 1.05 equiv.) and catalytic amount of DMF (0.1 mL) for 1 hour. Solvent and excess (COCl)2 were removed on rotary evaporator. The residue was dissolved in 100 mL dichloromethane, and treated with 1,3-dimethyl-5-aminoindole (2.40 g, 15.0 mmol, 1.00 equiv.) and triethylamine (2.28 g, 22.5 mmol, 1.50 equiv.) at 0° C. for one hour. Normal aqueous workup and removal of solvent gave a light brown solid that was washed with ether to yield 2,4-dibenzyloxy-5-isopropyl-N-(1-methyl-1H-indol-5-yl)-benzamide (A) as off-white solid (7.20 g, 14.3 mmol, 95%)
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].C1(C)C=CC(S(CCOC(=O)C)(=O)=O)=CC=1.[C:44]1([CH3:70])[CH:49]=[CH:48][C:47]([S:50]([CH2:53][CH2:54][O:55][C:56](=[O:69])[CH2:57][O:58][C:59]2[CH:64]=[CH:63][C:62]([S:65](Cl)(=[O:67])=[O:66])=[CH:61][CH:60]=2)(=[O:52])=[O:51])=[CH:46][CH:45]=1.C([O-])(O)=O.[Na+].ClS([O-])(=O)=O>C(Cl)Cl>[C:44]1([CH3:70])[CH:49]=[CH:48][C:47]([S:50]([CH2:53][CH2:54][O:55][C:56](=[O:69])[CH2:57][O:58][C:59]2[CH:64]=[CH:63][C:62]([S:65]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:66])=[O:67])=[CH:61][CH:60]=2)(=[O:52])=[O:51])=[CH:46][CH:45]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2ccc(S(=O)(=O)Cl)cc2)cc1
Agent: CC(=O)OCCS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCOC(=O)COc2ccc(S(=O)(=O)n3c(S(=O)Cc4nccc(OCC(F)(F)F)c4C)nc4ccccc43)cc2)cc1
Yield: 94 %

Procedure:
To a heterogeneous solution of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-ylmethanesulfinyl]-1H-benzimidazole (900 mg, 2.44 mmol) in 30 mL of CH2Cl2 was added 70 mg of NaH (2.92 mmol) at room temperature, during which time the mixture became homogeneous. To this clear reaction mixture was added the 4-chlorosulfonylphenoxy)acetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 4, 1.26 g, 2.92 mmol, 1.2 eq). About 1 g of solid NaHCO3 was added after the chlorosulfonate has dissolved completely in the reaction mixture. (Without addition of NaHCO3 the mixture became black when the reaction was complete.) Thereafter the solvent was removed by evaporation and the residual oil was purified by column chromatography (silica gel, CH2Cl2 to 4% MeOH in CH2Cl2) to give 1.75 g (94%) of the desired product (Intermediate 5) as an off-white foam.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11]/[C:12](=[C:19]1\[C:20](=[O:28])[NH:21][C:22]2[C:27]\1=[CH:26][CH:25]=[CH:24][CH:23]=2)/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].O1CCOCC1.[OH-].[Na+].Cl>CO>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11]/[C:12](=[C:19]1\[C:20](=[O:28])[NH:21][C:22]2[C:27]\1=[CH:26][CH:25]=[CH:24][CH:23]=2)/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccccc1N/C(=C1\C(=O)Nc2ccccc21)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C1Nc2ccccc2/C1=C(/Nc1ccccc1C(=O)O)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
176 mg (0.48 mmol) of (Z)-3-[1-(2-methoxycarbonyl-phenylamino)-1-phenyl-methylidene]-2-indolinone are dissolved in 15 ml of methanol and 2 ml of dioxane and after the addition of 1.4 ml of 1N sodium hydroxide solution stirred for two hours at 80° C. Then the mixture is neutralised 1.4 ml of 1N hydrochloric acid while being cooled, the product precipitated is suction filtered, washed with water and dried.
Reaction SMILES: [C:1]([O:5][C:6](=[O:58])[C:7]([O:10]/[N:11]=[C:12](/[C:44]1[N:45]=[C:46]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[S:47][C:48]=1[Cl:49])\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S@:18](=[O:43])[CH2:19][C:20]([CH2:41]Cl)=[C:21]2[C:25]([O:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[I-:59].[Na+]>CC(C)=O>[C:1]([O:5][C:6](=[O:58])[C:7]([O:10]/[N:11]=[C:12](/[C:44]1[N:45]=[C:46]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[S:47][C:48]=1[Cl:49])\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S@:18](=[O:43])[CH2:19][C:20]([CH2:41][I:59])=[C:21]2[C:25]([O:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)C[S@@](=O)[C@H]23)c(Cl)s1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CI)C[S@@](=O)[C@H]23)c(Cl)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.4 %

Procedure:
To a solution of (5R,6R,7R)-benzhydryl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5-oxide (10.5 g, 11.50 mmol) in acetone (120 mL) was added sodium iodide (2.58 g, 17.24 mmol). The mixture was stirred at room temperature over 1.5 h. LCMS indicated completion of the reaction. The solid was filtered off, the filtrate was concentrated under vacuum, the residue was purified twice by CombiFlash Rf automated silica gel chromatography (120 g column), eluting with EtOAc/Hexanes (0-45%) to afford (5R,6R,7R)-benzhydryl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetamido)-3-(iodomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5-oxide (7.5 g, 7.75 mmol, 67.4% yield) as a light brown foaming solid. LCMS: (M+H)+: 967.9.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[N:13][CH:12]=[C:11]3[CH2:18][CH2:19]CC(F)(F)F)[CH2:3][CH2:2]1.C(I)C>>[CH2:18]([C:11]1[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH:4]3[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]3)[CH:9]=2)[CH:14]=[N:13][CH:12]=1)[CH3:19]
Reactant: FC(F)(F)CCCc1cncc2ccc(OC3CCNCC3)cc12
Solvent: CCI
Product: CCc1cncc2ccc(OC3CCNCC3)cc12

Procedure:
The compound 266 was synthesized in a similar fashion as described for compound 90, using ethyl iodide. LCMS Method # 1, retention time 0.98 min, detected mass 257.31 [M+H]+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[N:2]2)=[CH:14][CH:13]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: c1ccc2[nH]ncc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-n2ncc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.7 %

Procedure:
A mixture of 1H-Indazole (0.50 g, 4.23 mmol), 4-methoxyphenylboronic acid (1.30 g, 8.5 mmol), triethylamine (0.86 g, 8.5 mmol) and cupric acetate ((0.77 g, 4.23 mmol) in CH2Cl2 (50 mL) was stirred at room temperature for 48 h. The reaction mixture was diluted with water and passed through a pad of Celite. The filtrate was extracted with EtOAc, washed with brine, and dried over Na2SO4. After being concentrated, the crude material was purified by a chromatography on silica gel to yield the title compound (0.32 g, 30%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>C(N(CC)CC)C>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:7]
Reactant: C1CCNCC1
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1cccc(CCl)c1)N1CCCCC1
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
3-Chloromethylbenzoyl chloride (1.45 ml) was added to a solution of piperidine (1 ml) in triethylamine (2 ml) and the mixture was stirred under nitrogen at 5° C. for 45 min. Water was added, the product was extracted with dichloromethane and the extract was washed with water, dried over sodium sulphate and evaporated to give 1(3-chloromethylbenzoyl)piperidine (2.32 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CCCBr
Reactant: CCOC(=O)Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCC(C(=O)OCC)c1ccccc1Cl
Temperature: 60 °C
Yield: 100 %

Procedure:
A mixture of ethyl 2-(2-chlorophenyl)acetate (11.32 g, 57.0 mmol), ethyl 4-bromobutanoate (33.3 g, 171 mmol) and Cs2CO3 (55.7 g, 171 mmol) in DMF (Volume: 57.0 ml) was heated at 60° C. overnight. The reaction was cooled to RT and diluted into a mixture of ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were concentrated in vacuo. The residue was purified by flash chromatography (SG, 0 to 45% EtOAc/Hex) to get diethyl 2-(2-chlorophenyl)hexanedioate (17.82 g, 57.0 mmol, 100% yield). LC-MS (M+H)+=313.2. 1H NMR (500 MHz, CD3OD) δ 7.41 (ddd, J=17.0, 7.7, 1.5 Hz, 2H), 7.33-7.24 (m, 2H), 4.21-4.07 (m, 4H), 2.34 (td, J=7.3, 2.1 Hz, 2H), 2.16-2.05 (m, 1H), 1.82 (dddd, J=13.4, 10.3, 7.7, 5.5 Hz, 1H), 1.70-1.48 (m, 2H), 1.33-1.25 (m, 1H), 1.24 (t, J=7.2, 7.2 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H).