Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([NH2:41])=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2C3C=CC(C(O)=O)=CC=3N3C[C:60]([C:62]([N:64]4[CH2:69]CC(N5CCOCC5)C[CH2:65]4)=[O:63])=CC4C=CC=CC=4C=23)CCCCC1.C(N(CC)C(C)C)(C)C.Cl.Cl.NCCC1NC2C=CC=CC=2N=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([NH:41][CH2:60][C:62]([N:64]([CH3:69])[CH3:65])=[O:63])=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NCCc1nc2ccccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)CNC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Yield: 34 %

Procedure:
N-[2-(]H-benzimidazol-2-yl)ethyl]-13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxamide. A solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (47 mg, 0.085 mmol), N,N-diisopropylethylamine (60 μL, 0.34 mmol), 2-(2-aminoethyl)benzimidazole dihydrochloride (23 mg, 0.1 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (23 mg, 0.12 mmol), and 1-hydroxybenzotriazole (16 mg, 0.12 mmol) in CH2Cl2 (3.1 mL) was stirred at r.t. overnight, then introduced directly to silica gel. Elution (gradient: 0%→5% MeOH in CH2C12) gave the title compound as a yellow powder (20 mg, 34% yield). LC/MS (ESI) retention time: 1.57 min, m/z 697 (MH+); 1H NMR (400 MHz, CDCl3) δ 1.09-1.21 (m, 1 H) 1.22-1.37 (m, 3 H) 1.38-1.48 (m, 1 H) 1.58-1.68 (m, 1 H) 1.69-1.76 (m, 2 H) 1.87 (t, 1 H) 1.97 (t, 2 H) 2.27 (t, J=10.95 Hz, 1 H) 2.39 (s, 3 H) 2.61-2.72 (m, 1 H) 2.72-2.82 (m, 1 H) 3.26 (t, J=6.04 Hz, 2 H) 3.61-3.70 (m, 4 H) 3.98 (s, 2 H) 4.18 (s, 1 H) 4.86 (s, 1 H) 6.80 (s, 1 H) 7.13 (dd, J=6.04, 3.27 Hz, 2 H) 7.33-7.38 (m, 2 H) 7.40-7.46 (m, 2 H) 7.46-7.53 (m, 3 H) 7.73 (d, J=8.56 Hz, 1 H) 7.77-7.85 (m, 1 H) 8.04 (s, 1 H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[Cl-].[Cl:22][CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:43]=[C:44]1[CH2:61][CH2:60][C@@:59]2([CH2:62][CH:63]=O)[C@@H:46]([CH2:47][CH2:48][C@@H:49]3[C@@H:58]2[CH2:57][CH2:56][C@@:54]2([CH3:55])[C@H:50]3[CH2:51][CH2:52][C:53]2=[O:65])[CH2:45]1>O1CCCC1.O>[Cl:22][CH:23]=[CH:63][CH2:62][C@@:59]12[C@@H:58]3[C@H:49]([C@H:50]4[C@@:54]([CH2:56][CH2:57]3)([CH3:55])[C:53](=[O:65])[CH2:52][CH2:51]4)[CH2:48][CH2:47][C@H:46]1[CH2:45][C:44](=[O:43])[CH2:61][CH2:60]2
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(=O)CC[C@@]43CC=O)[C@@H]1CCC2=O
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(=O)CC[C@@]43CC=CCl)[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of lithium diisopropylamide, prepared from 0.26 ml of diisopropylamine and 0.85 ml of a 2.1 M solution of butyllithium and 5 ml of tetrahydrofuran is added to a solution of 640 mg of (chloromethyl)triphenylphosphonium chloride in 5 ml of tetrahydrofuran at -70° C. After 10 minutes at -70° C., a solution of 560 mg of 3,17-dioxo-5α-androstane-19-carboxaldehyde in 4 ml of tetrahydrofuran is added and the mixture is allowed to warm to room temperature. The mixture is then poured into water and extracted with ether. The solvent is evaporated and the residue is purified by flash chromatography on silica gel in 50% ethyl acetate-hexane to give 10-(3-chloroprop-2-enyl)-5α-estrane-3,17-dione as a mixture of isomers.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](=O)[CH2:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.[Cl:15][C:16]1[C:17]([NH:23][NH2:24])=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=1>C(O)(=O)C>[Cl:15][C:16]1[C:17]([N:23]2[C:5]([C:7]3[O:8][CH:9]=[CH:10][CH:11]=3)=[CH:4][C:3]([C:2]([F:14])([F:13])[F:1])=[N:24]2)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: NNc1ncc(Cl)cc1Cl
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(-c2ccco2)n(-c2ncc(Cl)cc2Cl)n1
Yield: 60.9 %

Procedure:
To a 250 mL flask, 4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione (5.50 g, 26.7 mmol), 3,5-dichloro-2-hydrazinylpyridine (4.75 g, 26.7 mmol) and glacial acetic acid (100 mL) were added. The reaction mixture was heated to reflux. When the reaction completed, the reaction mixture was concentrated by rotary evaporator. Then ethyl acetate (300 mL) and water (150 mL) was added, the organic extracts were washed with saturated sodium bicarbonate solution (150 mL) and brine (150 mL) in sequence, dried over anhydrous magnesium sulfate and concentrated by rotary evaporator. The residue was purified by silica gel column chromatography (Fluent: ethyl acetate/petroleum ether=1/5) to give the product (5.66 g) as a yellow oil in 61% yield. 1H NMR (300 MHz, CDCl3): 8.514 (d, 1H), 7.974 (d, 1H), 7.362 (d, 1H), 6.917 (s, 1H), 6.388 (dd, 1H), 6.148 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1(NCC)[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:3]1.[Cl:16][C:17]1[C:21]([NH:22][C:23](=[O:25])[CH3:24])=[CH:20][N:19]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[N:18]=1.C(Br)C.[H-].[Na+].CC(C)([O-])C.[Na+].CC(C)([O-])C.[K+].C(OC(CC)(C)C)(CC)(C)C.[Na]>O1CCCC1>[Cl:1][C:2]1[C:6]([N:22]([CH2:21][CH3:20])[C:23](=[O:25])[CH3:24])=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.[Cl:16][C:17]1[C:21]([NH:22][C:23](=[O:25])[CH3:24])=[CH:20][N:19]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[N:18]=1
Reactant: CCNC1(Cl)C=CN(c2cccnc2)N1
Agent: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Agent: CC(C)(C)[O-]
Agent: CCC(C)(C)OC(C)(C)CC
Solvent: C1CCOC1
Solvent: CCBr
Product: CCN(C(C)=O)c1cn(-c2cccnc2)nc1Cl

Procedure:
3-Chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (1d) may be prepared through the reaction pathway sequence disclosed in Scheme 3. In step d1, N-(3-chloro1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (1c) may be alkylated with ethyl bromide (EtBr) in the presence of a base, such as sodium hydride (NaH), sodium tert-butoxide (NaOt-Bu), potassium tert-butoxide (KOt-Bu), or sodium tert-amyloxide, in a polar aprotic solvent, such as tetrahydrofuran, at temperatures from about 20° C. to about 40° C., over a period of time of about 60 hours to about 168 hours, to yield N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1c′). It has been discovered that use of an iodide additive, such as potassium iodide (KI) or tetrabutylammonium iodide (TBAI) can decrease the time necessary for the reaction to occur to about 24 hours. It has also been discovered that heating the reaction at about 50° C. to about 70° C. in a sealed reactor (to prevent loss of ethyl bromide) also decreases the reaction time to about 24 hours. In step d2, N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1c′) may be treated with hydrochloric acid in water at temperatures from about 50° C. to about 90° C., to yield 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (1d). The reaction pathway sequence disclosed in Scheme 3 may also be performed without the isolation of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1c′).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]1[C:18]([CH3:19])=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=1[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:27]C=2C=1.CCN=C=NCCCN(C)C.Cl.N>C(O)(C)C>[C:1]([O:5][C:6](=[O:7])[CH2:8][CH2:9][C:10]1[C:18]([CH3:19])=[CH:17][C:13]([C:14](=[O:15])[NH2:27])=[CH:12][C:11]=1[CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)O)cc(C)c1CCC(=O)OC(C)(C)C
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CC(C)O
Product: Cc1cc(C(N)=O)cc(C)c1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a suspension of 4-(2-tert-butoxycarbonyl-ethyl)-3,5-dimethyl-benzoic acid (8.00 g, 28.7 mmol) in isopropanol (100 mL), HOBt (4.27 g, 31.6 mmol) followed by EDC hydrochloride (6.34 g, 33.1 mmol) is added. After stirring at rt for 1 h, 25% aq. ammonia (16.1 mL) is added. Stirring is continued for 30 min before the isopropanol is evaporated under reduced pressure. The remaining solution is diluted with isopropyl acetate (200 mL), washed three times with approximately 0.5 N aq. NaHCO3 solution (100 mL) followed by water (50 mL), dried over MgSO4, filtered, concentrated and dried to give 3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid tert-butyl ester (7.5 g) as an off-white solid.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[O:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>>[O:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[N:13]1[CH2:14][CH:15]2[CH2:16][N:9]([C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:8])[CH2:10][CH:11]2[CH2:12]1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Reactant: Clc1nc2ccccc2o1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3nc4ccccc4o3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-benzooxazole. MS (ESI): mass calculated for C26H23N3O2, 409.49; m/z found 410.2 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4](Cl)=[O:5].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]2[N:26]([CH3:37])[C:27]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH2:36])[N:31]=3)=[C:28]([I:29])[C:22]=2[C:21]1=[O:38])=[O:19])([CH3:16])([CH3:15])[CH3:14].N1C=CC=CC=1>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]2[N:26]([CH3:37])[C:27]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([N:36]4[C:4](=[O:5])[C:3]5[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:1]4=[O:11])[N:31]=3)=[C:28]([I:29])[C:22]=2[C:21]1=[O:38])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: Cn1c2c(c(I)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1c2c(c(I)c1-c1ccnc(N3C(=O)c4ccccc4C3=O)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
Pthaloyl chloride (0.089 g, 0.437 mmol) was added to a cold (0° C.) solution of 2-(2-Amino-pyrimidin-4-yl)-3-iodo-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo-[3,2-c]-pyridine-5-carboxylic acid tert-butyl ester (prepared as described in Example 1) (0.158 g, 0.337 mmol) and pyridine (0.069 g, 0.875 mmol) in dry DCM (1.5 ml) and the reaction mixture was stirred at room temperature in argon atmosphere for 4 h. The organic layer was washed with a saturated solution of NaHCO3 (1×2.0 ml), brine (1×2.0 ml), and it was dried over Na2SO4. The filtrate was evaporated to dryness to give the crude product, which was purified by flash chromatography, over silica gel (DCM/MeOH (9.8:0.2) as eluent), to afford 2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pyrimidin-4-yl]-3-iodo-1-methyl-4-oxo-1,4,6,7-tetra-hydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.150 mg, 0.25 mmol, 74%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]Cl)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:36].[Na+]>CC(C)=O>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][I:36])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [I-]
Reactant: COc1ccc(COC(=O)C2=C(C=CCCl)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(C=CCI)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Yield: 60.4 %

Procedure:
After 20.0 g of p-methoxybenzyl 7β-[2-phenylacetamido]-3-[3-chloro-1-propenyl]-3-cephem-4-carboxylate (E/Z=25/75) was suspended in 250 ml of acetone, 29 g of sodium iodide was added to the suspension. The mixture was reacted at 25°-30° C. for 3 hours, while stirring. After the reaction was completed, the solution was concentrated at a temperature below 25° C. under a reduced pressure of 100 mmHg and 60 ml of acetone was distilled off. The formed crystals were collected by filtration and washed successively with 50 g of 5% sodium thiosulfate aqueous solution, next with 50 g of ion exchange water and finally with 50 g of acetone to give 14.24 g of p-methoxybenzyl 7β-[2-phenylacetamido]-3-[3-iodo-1-propenyl]-3-cephem-4-carboxylate (content, 97.0%; E/Z=99/1). The yield of E-form was 59%.
Reaction SMILES: O1C2C=CC=C[C:4]=2[CH:3]=N1.[OH:10][C:11]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[O:13][N:12]=1.C(O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:3]([O:10][C:11]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[O:13][N:12]=1)[CH3:4]
Reactant: c1ccc2oncc2c1
Reactant: COc1ccc2c(O)noc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1noc2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Benzisoxazole from part (b) (193 mg, 1.17 mmol), ethanol (75 μl, 1.29 mmol) and triphenylphosphine (460 mg, 1.75 mmol) were dissolved in anhydrous THF (4 ml) and cooled (0°). Diisopropylazodicarboxylate (345 μl, 1.75 mmol) was added slowly and after 10–15 min the reaction flask was removed from the ice bath and the reaction mixture was stirred at room temperature overnight under an argon atmosphere. The solution was evaporated to dryness and the residue pre-absorbed onto silica, and chromatographed on silica (19 g); eluent: hexane (300 ml), 10–30% ethyl acetate/hexane to give 3-ethoxy-6-methoxy-1,2-benzisoxazole (101 mg, 44%) as white crystals.
Reaction SMILES: [C:1]([C-:3]([C:6]#[N:7])[C:4]#[N:5])#[N:2].[K+].CS(O)(=O)=O.[CH:14]([OH:17])([CH3:16])[CH3:15]>>[NH2:2][C:1]([O:17][CH:14]([CH3:16])[CH3:15])=[C:3]([C:6]#[N:7])[C:4]#[N:5]
Reactant: CC(C)O
Reactant: N#C[C-](C#N)C#N
Agent: CS(=O)(=O)O
Agent: [K+]
Product: CC(C)OC(N)=C(C#N)C#N

Procedure:
In the manner of Example V A, 129.2 g of potassium tricyanomethanide and 1000 ml of isopropanol were treated with 65 ml (96 g) of methanesulfonic acid to yield 104 g of 3-amino-2-cyano-3-isopropoxy-2-propenenitrile, which was used as an intermediate without further purification. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[CH3:24])=O)=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[CH3:24])=[CH:11][CH:10]=1
Reactant: Cc1cc(O)ccc1C(=O)c1ccc(Br)cc1
Reactant: O=C1CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(O)ccc1C(=C1CCCCC1)c1ccc(Br)cc1
Yield: 81.5 %

Procedure:
To a slurry of zinc powder (1.15 g, 17.59 mmol) in THF (10 mL) was added TiCl4 (0.90 mL, 8.21 mmol) dropwise. The mixture was heated at reflux for 1 h. A mixture of cyclohexanone (0.64 mL, 6.17 mmol) and (4-bromophenyl)(4-hydroxy-2-methylphenyl)methanone (28) (0.60 g, 2.06 mmol) in THF (10 mL) was added dropwise and continued to stir at reflux for 20 min. Upon cooling, the reaction mixture was poured into a 10% aqueous K2CO3 solution. The quenched reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc. The filtrate was dried over MgSO4, filtered, and concentrated to yield 0.60 g (81%) of the compound 29. 1H NMR (400 MHz, CDCl3): δ 1.50-1.63 (m, 6H), 1.96-2.01 (m, 2H), 2.05 (s, 3H), 2.27-2.28 (m, 2H), 4.54 (s, 1H), 6.60-6.62 (m, 2H), 6.93-6.95 (m, 1H), 6.98 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:29])[F:28].CC([O-])(C)C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[CH2:16][CH2:15]1)(=[O:12])=[O:13]
Reactant: FC(F)(F)c1ccccc1Br
Reactant: O=S(=O)(c1ccc2ccccc2c1)C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc2ccccc2c1)C1CCN(c2ccccc2C(F)(F)F)CC1
Temperature: 90 °C
Yield: 50.1 %

Procedure:
A 5 mL microwave reaction vial was charged with 4-(2-naphthylsulfonyl)piperidine (82 mg, 0.30 mmol), 2-bromobenzotrifluoride (67 mg, 0.30 mmol), NaOt-Bu (40 mg, 0.42 mmol), Pd2(dba)3 (26 mg, 0.025 mmol), racemic BINAP (31 mg, 0.05 mmol), and dioxane (1.5 mL). The mixture was degassed with N2, capped, and heated in a 90° C. oil bath for 16 h. The mixture was diluted with CH2Cl2 (10 mL) and filtered through a plug of SiO2. The organic phase was concentrated and purified by SiO2 chromatography (15 to 30% EtOAc-hex) to afford the title compound (63 mg), a yellow oil, in 50% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[C:25]([CH3:32])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(OCC)(=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.C1(C)C=CC=CC=1.C(O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:21]=[CH:20][CH:19]=[C:4]([CH2:5][O:6][C:7]3[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=3)[CH:3]=2)=[C:25]([CH3:32])[CH:24]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Reactant: Cc1cc(Cl)ccc1B(O)O
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: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCc2cccc(-c3ccc(Cl)cc3C)c2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
A mixture of methyl 3-[4-[(3-bromobenzyl)oxy]phenyl]propanoate (0.5 g, 1.43 mmol), 4-chloro-2-methylphenylboronic acid (0.30 g, 1.72 mmol), tetrakis(triphenylphosphine)palladium(0) (0.083 g, 0.072 mmol), sodium carbonate (0.46 g, 4.29 mmol), water (5 mL), ethanol (5 mL) and toluene (25 mL) was stirred under an argon atmosphere at 90° C. for 16 hrs. The reaction mixture was cooled, diluted with ethyl acetate, washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-4/1) to give the title compound (0.50 g, yield 88%) as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[C:7](=[O:21])[CH:8]=[C:9]([C:16]([O:18]CC)=[O:17])[NH:10][C:11]=2[C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:4].[OH-].[K+]>C(O)C>[Cl:15][C:12]1[C:11]2[NH:10][C:9]([C:16]([OH:18])=[O:17])=[CH:8][C:7](=[O:21])[C:6]=2[C:5]([C:3]([OH:4])=[O:2])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cc(=O)c2c(C(=O)OC)ccc(Cl)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(=O)c2c(C(=O)O)ccc(Cl)c2[nH]1
Temperature: 100 °C

Procedure:
To a solution of 24 (10.0 g, 32.3 mmol) in ethanol (100 mL) was added 10% aqueous KOH solution (100 mL) at room temperature. The reaction mixture was heated at 100° C. for 24 h and then cooled to room temperature. The reaction mixture was concentrated in vacuum. The resulting aqueous solution was acidified with 2N HCl to pH=6.5, where a solid precipitated and was collected through a filtration. The solid was washed with H2O (100 mL) and Et2O (100 mL), and dried in vacuum at 60° C. to give an off-white solid (25, 8.00 g, 92.9%). 1H NMR (DMSO-d6, 300 MHz) δ ?7.97 (d, J=7.8 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 6.90 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:9]([N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)=[O:4].C(N(CC)C(C)C)(C)C.[C:40]1([C@@H:46]([CH2:48][OH:49])[NH2:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1COCC1>[OH:4][C@H:3]([C:5]1[CH:6]=[CH:7][C:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:9]([N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[CH2:2][NH:47][C@@H:46]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:48][OH:49]
Reactant: N[C@H](CO)c1ccccc1
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)N(Cc1ccccc1)c1cc([C@@H](O)CN[C@H](CO)c2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.4 %

Procedure:
A solution of N-{5-(bromoacetyl)-2-[(phenylmethyl)oxy]phenyl}-N-(phenylmethyl) methanesulfonamide (570 mg) in THF (15 ml) was treated with N,N-diisopropylethylamine (0.41 ml) and (S)-(+)-2-phenylglycinol (191.8 mg). The mixture was stirred at room temperature for 5 h. The solvent was removed in vacuo and the resulting solid was suspended in dry MeOH (15 ml). The resulting suspension was cooled to 0°, treated with calcium carbonate (359 mg) and stirred for 0.5 h. The reaction mixture was treated with NaBH4 (88.8 mg), portionwise at 0° and was then allowed to warm to room temperature and stirred for 64 h. The mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic phase was dried (MgSO4) and concentrated in vacuo. The mixture was purified by column chromatography (SPE, gradient 0 to 15% [MeOH-ammonia (10:1)] in DCM) to afford the title compound (360 mg).
Reaction SMILES: Cl[C:2](=[O:9])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:10][O:11][CH:12]([O:32][CH3:33])[CH:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28](=[NH:31])[NH:29]O)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH2:14]1.N1C=CC=CC=1>>[CH3:8][O:7][C:5](=[O:6])[CH2:4][CH2:3][C:2]1[O:9][N:31]=[C:28]([C:25]2[CH:26]=[CH:27][C:22]([S:19]([N:16]3[CH2:17][CH2:18][CH:13]([CH:12]([O:11][CH3:10])[O:32][CH3:33])[CH2:14][CH2:15]3)(=[O:21])=[O:20])=[CH:23][CH:24]=2)[N:29]=1
Reactant: COC(OC)C1CCN(S(=O)(=O)c2ccc(C(=N)NO)cc2)CC1
Reactant: COC(=O)CCC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)CCc1nc(-c2ccc(S(=O)(=O)N3CCC(C(OC)OC)CC3)cc2)no1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Methyl 4-chloro-4-oxobutanoate (0.391 g, 2.6 mmol), 4-{[4-(dimethoxy-methyl)-1-piperidinyl]sulfonyl}-N-hydroxybenzenecarboximidamide (0.480 g, 1.3 mmol) was dissolved in 4 mL (49.5 mmol) of pyridine and stirred at 85° C. overnight. The solvent was evaporated with toluene, and the reaction mixture was partitioned between chloroform and water. The organic layer was washed with brine and dried with sodium sulfate. The final product was purified my flash chromatography (chloroform-methanol, 50:1) to give 0.130 g (0.22 mmol).