Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[OH:10][CH2:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:16]2[CH:17]=[C:12]([CH2:11][OH:10])[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: BrCc1ccc(Br)cc1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: OCc1cccc(Cc2ccc(Br)cc2)c1
Yield: 85 %

Procedure:
4-Bromobenzyl bromide (6.1 g, 22 mmol) and [3-(hydroxymethyl)phenyl]boronic acid (3.0 g, 20 mmol) were dissolved in a mixed solvent of toluene (40 mL), ethanol (30 mL) and water (20 mL), and tetrakis(triphenylphosphine)palladium (1.1 g, 1.0 mmol) and sodium carbonate (4.2 g, 40 mmol) were added under a nitrogen atmosphere, followed by heating to reflux for 6 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.75 (hexane/ethyl acetate=1/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (4.7 g, 17 mmol) as a yellow oil (yield 85%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10])([O-:3])=[O:2].[CH2:15](Cl)[CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:15]([O:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:12][CH3:13])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCCl
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(OC)cc(C=O)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 5-nitrovanillin (2.2 g), butyl chloride (10 ml), potassium carbonate (8 g) and N,N-dimethylformamide (50 ml) is stirred at 100° C. for 24 hours. After cooling, water (300 ml) is added to the reaction mixture, followed by extraction with ethyl acetate (200 ml). The extract solution is washed with water, dried, and concentrated under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane: ethyl acetate=1:1) to afford 4-butoxy-3-methoxy-5-nitrobenzaldehye (2 g) as a pale yellow oily product. This product is dissolved in acetone (100 ml), potassium permanganate (6 g) is added to the mixture, and the mixture is stirred at room temperature overnight. To the reaction mixture are added ethanol (20 ml), water (20 ml) and acetone (200 ml). The whole mixture is left standing for two hours, then insolubles are filtered off. The filtrate is concentrated under reduced pressure. The concentrate is dissolved in water (100 ml) and the mixture is acidified with concentrated hydrochloric acid. Precipitating crystals are collected by filtration to afford 4-butoxy-3-methoxy-5-nitrobenzoic acid (1.6 g) as colorless crystals. This product is recrystallized from a mixture of ethanol and water to give colorless prisms, m.p. 114°-115° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[Li]CCCC.C(O[B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]1)(C)C>C1COCC1.[NH4+].[Cl-]>[CH3:1][N:2]1[C:6]([B:16]2[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]2)=[CH:5][CH:4]=[N:3]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cn1cccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a solution of 1-methylpyrazole (4.1 g, 50 mmole) in THF (100 mL) at 0° C. was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to −78° C. [J. Heterocyclic Chem. 41, 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.3 mL, 60 mmole). After 15 min at −78° C., the reaction was allowed to warm to 0° C. over 1 hour. The reaction was diluted with saturated NH4Cl solution and extracted with DCM. The organics were dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 76%) which was used without further purification. LCMS (ES) m/z 127 (M+H)+ for [RB(OH)2]; 1H NMR (CDCl3, 400 MHz) δ 7.57 (s, 1H), 6.75 (s, 1H), 4.16 (s, 3H), and 1.41 (s, 12H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.O.Cl[C:20](OCC)=O.[CH:25]1([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2(C)[CH2:36][NH2:37])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(N(CC)CC)C.CC(C)=O>[CH:25]1([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[CH:36]([CH3:20])[NH:37][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])[C:10]([NH2:12])=[CH:11][C:3]=2[O:2][CH3:1])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCS(=O)(=O)c1cc(C(=O)O)c(OC)cc1N
Reactant: CCOC(=O)Cl
Reactant: CC1(CN)CCCN1C1CCCCC1
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)c1cc(C(=O)NC(C)C2CCCN2C2CCCCC2)c(OC)cc1N
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
25.9 g of 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid, 40 ml of water, 200 ml of acetone and 13.9 ml of triethylamine (density 0.726) are placed in a 500 ml flask fitted with an agitator, a thermometer and a dropping funnel. The solution is cooled to about 0° to 5° C. and 10.9 g of ethyl chloroformate is dripped in. The mixture is agitated for 40 minutes at about 0° C., then 19.6 g of 1-cyclohexyl-methyl-2-aminomethyl pyrrolidine is added drop by drop. The mixture is agitated for 2 hours at room temperature then left to stand. The acetone is evaporated under vacuum and the residue is dissolved in 100 ml of water and 25 ml of acetic acid and filtered in the presence of vegetable black. The filtrate is made alkaline with 100 ml of 40% soda lye. A precipitate is formed; this is filtered, washed with plenty of water and dissolved moist in 230 ml of boiling acetone. The hot solution is filtered in the presence of vegetable black and the filtrate is crystallised. The product is drained, washed with a little acetone and dried in an oven at 50° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:27][CH:28]2[CH2:30][CH2:29]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[NH:38][C:37](=[O:42])[CH2:36][CH2:35]2.C[Si](Cl)(C)C>C(O)CCC>[CH:28]1([NH:27][C:4]2[C:5]3[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:31][C:32]3[CH:33]=[C:34]4[C:39](=[CH:40][CH:41]=3)[NH:38][C:37](=[O:42])[CH2:36][CH2:35]4)[N:3]=2)[CH2:30][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: O=C1CCc2cc(Nc3nc(NC4CC4)c4c(-c5ccncc5)c[nH]c4n3)ccc2N1
Temperature: 135 °C
Reaction time: 18 h
Yield: 6.4 %

Procedure:
A mixture of 2-chloro-N-cyclopropyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (85 mg, 0.19 mmol), 6-amino-3,4-dihydroquinolin-2(1H)-one (70 mg, 0.43 mmol) and TMSCl (0.100 mL, 0.79 mmol) in nBuOH (3 mL) was stirred at 135° C. for 18 h. More TMSCl (0.200 mL) was added. Stirring was continued at 135° C. for another 68 h. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (5 mg). MS 412.3 (M+H); UV 201.8, 295.8 nm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:1][C:2]2[CH:7]=[N:6][N:5]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][O:9]3)[C:4](=[O:14])[CH:3]=2)=[N:18][CH:19]=1
Reactant: O=c1cc(O)cnn1C1CCCCO1
Reactant: Fc1ccc(CBr)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1cc(OCc2ccc(F)cn2)cnn1C1CCCCO1
Yield: 26.9 %

Procedure:
5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.62 g, 13.4 mmol) (this compound was prepared in accordance with the procedure of Stenkamp et al., WO 2008022979), 2-(bromomethyl)-5-fluoropyridine (7.6 g, 40.2 mmol) and K2CO3 (9.24 g, 67 mmol) were stirred in DMF (40 ml) and CH2Cl2 (40 ml) for 48 h. The mixture was diluted with CH2Cl2, washed with 5% LiCl solution (4×) and concentrated. The residue was purified by column chromatography (40 g ISCO column column eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 95% methylene chloride) to yield the title compound (1.1 g, 27%) as a light brown solid: 1H NMR (300 MHz, CDCl3) δ 8.47 (s, 1H), 7.73 (d, J=2.9 Hz, 1H), 7.47-7.43 (m, 2H), 6.19 (d, J=2.9 Hz, 1H), 6.03-5.98 (dd, J=10.7, 2.0 Hz, 1H), 5.12 (s, 2H), 4.18-4.08 (m, 1H), 3.78-3.69 (td, J=11.6, 2.6 Hz, 1H), 2.21-2.00 (m, 2H), 1.75-1.60 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:8][C:4]=1[C:5]([OH:7])=O.CC(C)=O.ClC(OCC(C)C)=O.[CH:30]1([CH2:33][N:34]2[CH2:38][CH2:37][CH:36]([CH2:39][NH2:40])[CH2:35]2)[CH2:32][CH2:31]1>O.C(N(CC)CC)C>[CH:30]1([CH2:33][N:34]2[CH2:38][CH2:37][CH:36]([CH2:39][NH:40][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:10]=[C:11]([O:12][CH3:13])[C:3]=3[O:2][CH3:1])[CH2:35]2)[CH2:31][CH2:32]1
Reactant: NCC1CCN(CC2CC2)C1
Reactant: COc1cc(S(N)(=O)=O)cc(C(=O)O)c1OC
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(S(N)(=O)=O)cc(C(=O)NCC2CCN(CC3CC3)C2)c1OC

Procedure:
6.6 g of 2,3-dimethoxy-5-sulphamoyl benzoic acid, 50 ml of acetone, 10 ml of water and 3.6 ml of triethylamine (density 0.726) are placed in a 250 ml flask fitted with an agitator, a thermometer and a dropping funnel. The solution is cooled to 0°-+5° C. and 3.6 g of isobutyl chloroformate is poured in drop by drop. It is reacted for 30 minutes with the same temperature maintained, after which 4.8 g of 1-cyclopropylmethyl-3-aminomethyl-pyrrolidine is added drop by drop. The reaction medium is agitated for 1 hour at room temperature, whereupon 50 ml of water is added and the acetone evaporated under vacuum. A further 50 ml of water is added and the solution is made alkaline with 5 ml of ammonia (density=0.91). An oil is precipitated. The suspension is extracted 3 times with 50 ml of methylene chloride. The organic phase is dried over magnesium sulphate, filtered, then evaporated under vacuum. The residue is dissolved in boiling ethyl acetate. It crystallises hot. The crystals are cooled, filtered and dried in an oven at 50° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10]O)[C:5]=2[CH:6]=1.C(=O)=O>[OH-].[Na+]>[CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][C:7]3[C:5]4[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=4[NH:9][CH:8]=3)[C:5]=2[CH:6]=1
Reactant: OCc1c[nH]c2ccccc12
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2c(Cc3c[nH]c4ccccc34)c[nH]c2c1
Yield: 77.7 %

Procedure:
Part (a). Indole-3-carbinol (1.0 g, 6.79 mmol) in 10% aqueous NaOH solution (100 mL) was refluxed for 1 h. The solution was cooled, neutralized with carbon dioxide and the white precipitate was collected by filtration, which was then crystallized from toluene to yield 3,3′-Diindolylmethane as a white solid (0.65 g, 77%): 1H NMR (300 MHz, CDCl3) δ 4.26 (s, 2, CH2), 6.94 (m, 2, PyH), 7.11 (m, 2, ArH), 7.21 (m, 2, ArH), 7.36 (m, 2, ArH), 7.64 (m, 2, ArH), 7.86 (br. s, 2, NH).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C@@H:13]([NH:20][C:21]([C:23]2[CH:27]=[C:26]([OH:28])[N:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:24]=2)=[O:22])[CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:42]([O:44][C:45]([C:47]1(Br)[CH2:50][CH2:49][CH2:48]1)=[O:46])[CH3:43]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C@@H:13]([NH:20][C:21]([C:23]2[CH:27]=[C:26]([O:28][C:47]3([C:45]([O:44][CH2:42][CH3:43])=[O:46])[CH2:50][CH2:49][CH2:48]3)[N:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:24]=2)=[O:22])[CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCS(C)(=O)=O)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCS(C)(=O)=O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 100 mg of 4-{(S)-2-[(5-Hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-4-methanesulfonyl-butyryl}-piperazine-1-carboxylic acid ethyl ester in 2 ml of DMF, 127 mg of cesium carbonate and 81 mg of 1-Bromo-cyclobutanecarboxylic acid ethyl ester was added and heated to 100° C. for 2 h. Then, the reaction mixture was diluted with water and filtered through a Chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([CH2:19][CH3:20])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8](O)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[CH2:22]([Mg]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.CCOCC.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([CH2:19][CH3:20])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CCC1(CC(=O)OC)OCC(O)c2c1[nH]c1ccccc21
Reactant: Br[Mg]Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCC1(CC(=O)OC)OCC(Cc2ccccc2)c2c1[nH]c1ccccc21
Temperature: -78 °C
Yield: 51.5 %

Procedure:
To a solution of 1-ethyl-4-hydroxy-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid methyl ester (1 g, 3.6 mmol) in 60 mL of dry methylene chloride at -78° C. under nitrogen was added TiCl4 in one portion and then after ~10 minutes, a solution of benzyl magnesium bromide in ether was added in one portion and the reaction mixture was allowed to stir at -78° C. for ~30 minutes. The reaction was quenched with methanol (3 mL) at -78° C. and then poured into water (10 mL). The two layers were separated and the aqueous layer was then extracted with methylene chloride (2×100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was passed through a pad of silica gel, eluting with 10% EtOAc in hexane to give 0.67 g (51.5%) of the product as an oil, which had isomer ratio of 75:25 by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[CH2:7][C:8](=[O:28])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:27])[CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH2:25])=[C:20]([Cl:26])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Se](=O)=[O:34]>>[CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[C:7](=[O:34])[C:8](=[O:28])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:27])[CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH2:25])=[C:20]([Cl:26])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: O=[Se]=O
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Cl)c(N)c(Cl)c1)CC2
Product: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCN(C)CCc1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
This compound was prepared analogous to Example 5(b) from 1-[7,8dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl]-3-[N-methyl-N-(2-{4-amino-3,5-dichloro-phenyl}-ethyl)-amino]-propane and selenium dioxide.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9].[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22](F)=[C:21]([Cl:26])[CH:20]=1)(=[O:18])=[O:17].[OH-].[Na+]>CN(C=O)C>[Cl:26][C:21]1[CH:20]=[C:19]([S:16]([CH3:15])(=[O:18])=[O:17])[CH:24]=[CH:23][C:22]=1[O:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)COc1ccccc1O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2ccccc2OCC(=O)O)c(Cl)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% disp. oil, 0.24 g) was added to a solution of (2-hydroxyphenoxy)acetic acid (0.5 g) in DMF (20 ml) and stirred at 40° C. for 30 min. The product from example 7 step (ii) (0.62 g) was added, then the mixture heated at 75° C. for 30 h. 2M Sodium hydroxide solution was added and extracted with ethylacetate. The aqueous layer was acidified with 2M hydrochloric acid and extracted with ethyl acetate. The organics were dried, evaporated under reduced pressure and the residue purified by RPHPLC, yield 0.21 g.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:28]1>CS(C)=O.C(OCC)(=O)C.CCCCCC>[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([N:36]2[CH2:37][CH2:38][N:39]([CH2:11][CH:12]3[O:25][C:16]4=[C:17]5[C:21](=[CH:22][CH:23]=[C:15]4[O:14][CH2:13]3)[NH:20][C:19](=[O:24])[CH2:18]5)[CH2:40][CH2:41]2)=[N:28]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1Cc2c(ccc3c2OC(CN2CCN(c4nsc5ccccc45)CC2)CO3)N1
Temperature: 25 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.0 g, 2.7 mmole) and 1-(1,2-benzisothiazol-3-yl)piperazine (2.2 g, 10 mmole) are combined in 30 ml of dry DMSO and heated at 80°-90° C. for 4 hours under an argon atmosphere. After cooling to room temperature, the mixture is diluted with 500 ml of 1:1 ethyl acetate/hexane and washed with 250 ml of saturated aqueous sodium bicarbonate and with two 250 ml portions of water, dried over sodium sulfate, filtered and concentrated in vacuum. The residue is column chromatographed on silica gel using 0.5% methanol/CHCl3 as eluant to give the free base of the title compound. The product is crystallized from ethanol with the addition of one equivalent of fumaric acid to give the (S) enantiomer of the title compound as a fumarate salt.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(OCC)(=O)C>[CH3:23][S:24]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Benzyl 1-piperazinecarboxylate (2.03 g, 9.22 mmol) was dissolved in pyridine (23.0 mL, 9.22 mmol) and cooled to 0° C. before methanesulfonyl chloride (2.85 mL, 36.9 mmol) was added. The reaction mixture was stirred at 0° C. for 30 minutes and warmed to RT for 2 h. The reaction mixture was diluted with 75 mL of ethyl acetate, added to a separation funnel, partitioned with 3 N HCl (aqueous), washed 3× with 50 mL of 3 N HCl (aqueous), and separated, before the aqueous layer was extracted 3× with chloroform/isopropanol, then dried over sodium sulfate, and concentrated in vacuo to give the title compound. Benzyl 4-(methylsulfonyl)piperazine-1-carboxylate (2.80 g, 9.4 mmol) was dissolved in ethanol (0.43 g, 9.4 mmol) before palladium, 10 wt. % on activated carbon (2.0 g) was added and a hydrogen balloon attached. The reaction mixture was stirred at RT for 2 h before it was filtered through a pad of Celite®, washed with methanol, and concentrated in vacuo to give the title compound. MS (ES+): 165 (M+H)+.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[Li+].[Cl-].C1CCN2C(=NCCC2)CC1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:37]2[C:45]3[C:40](=[C:41]([N:46]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[S:47]([CH3:50])(=[O:49])=[O:48])[CH:42]=[CH:43][CH:44]=3)[CH:39]=[N:38]2)([CH2:35][CH3:36])[CH:33]=O)=[CH:28][CH:27]=1>CC#N>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:37]2[C:45]3[C:40](=[C:41]([N:46]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:56])[CH3:57])[S:47]([CH3:50])(=[O:49])=[O:48])[CH:42]=[CH:43][CH:44]=3)[CH:39]=[N:38]2)([CH2:35][CH3:36])/[CH:33]=[CH:3]/[C:1]#[N:2])=[CH:28][CH:27]=1
Reactant: CCC(C=O)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of diethyl cyanomethylphosphonate (20 mg, 0.12 mmol), LiCl (5 mg, 0.12 mmol) and DBU (18 mg, 0.12 mmol) in MeCN (2 mL) was added a solution of N-(1-(2-(4-chlorophenyl)-1-oxobutan-2-yl)-1H-indazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl) methane sulfonamide (50 mg, 0.10 mmol) in MeCN (1 mL). The mixture was stirred at room temperature for 2 h and evaporated. The residue was purified by silica gel chromatography (PE/EA=6/1) to afford the title compound as a white solid. LC/MS m/z=545.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:20]([OH:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@@H:19]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:20]([OH:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C[C@H](O)[C@@H](N)Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoate (Novabiochem), the title compound was prepared as a solid. The action was monitored by tlc (Rf=0.2 in 95:5 CHCl3/MeOH) and the product was purified by flash column chromatography using 95:5 CHCl3/MeOH as the eluent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:17]3[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Brc1ccc2ncc(I)n2c1
Product: FC(F)(F)c1ccc(-c2cnc3ccc(Br)cn23)cc1

Procedure:
The title compound, light brown solid (0.3 g, 40%), MS (ISP) m/z=341.4 [(M+H)+], mp 151° C., was prepared in accordance with the general method of intermediate E from commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (0.45 g, 2.38 mmol).