Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](/[CH:16]=[C:17](\[CH3:21])/[C:18]([OH:20])=[O:19])=[C:4]([O:14]C)[C:5]2[C:10]([C:11]=1[O:12]C)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N+]([O-])(O)=O.O>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:14])[C:3]=1/[CH:16]=[C:17](\[CH3:21])/[C:18]([OH:20])=[O:19]
Reactant: COc1c(Cl)c(/C=C(\C)C(=O)O)c(OC)c2ccccc12
Solvent: O=[N+]([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C/C(=C\C1=C(Cl)C(=O)c2ccccc2C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Following a modified procedure by Snyder et al.,33 dimethoxynaphthalene 42a (0.146 g, 0.476 mmol) and Ag(II)O (0.434 g, 3.51 mmol) were combined in a 5 mL round bottom flask and suspended in dioxane (1.5 mL). To the black suspension was added 6 M HNO3 (1.0 mL, 6.0 mmol) at room temperature. The black Ag(II)O quickly dissolved with gas evolution resulting in a yellow solute with yellow precipitate. The reaction was stirred for 10 minutes at room temperature and TLC showed no starting material present. The suspension was first filtered and the filter cake was suspended in CH2Cl2, treated with water, separated, washed with brine, dried, filtered, and condensed. The yellow reaction filtrate was likewise diluted with CH2Cl2, treated with water, separated, washed with brine, dried over MgSO4, filtered, and condensed. The filter cake provided pure 43a that was then purified by recrystallization from acetone/hexane (0.0601 g, 0.22 mmol, 47%). The filtrate provided a less pure 43a that was first purified by flash chromatography (1:4 EtOAc:hexanes 0.5% AcOH) and then recrystallized from acetone/hexane (0.027 g, 0.099 mmol, 21%).
Reaction SMILES: O=O.[CH-]=O.[CH-]=O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Co:19].[Co+2].[C:21]([OH:24])(=[O:23])[CH3:22]>>[C:21]([O-:24])(=[O:23])[CH3:22].[Co+2:19].[C:21]([O-:24])(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: [Co]
Agent: [Co+2]
Agent: O=O
Agent: [C-]#[O+]
Product: CC(=O)[O-]

Procedure:
The C12–C14 α-olefin mixture from Example 1 with the composition shown in Table I was hydroformylated in the manner indicated in Example 1. Unlike Example 1, instead of the rhodium catalyst and the polyethyleneimine ligand, the hydroformylation catalyst used was dicobaltoctacarbonyl without any other ligand, the amount being 2 g of cobalt based on 1000 g of reactor contents. In order that the olefin conversion obtained was from 98 to 99%, as in Example 1, using the same olefin feed, a reactor temperature of 140° C. was required in both reactors. The (aldehyde+alcohol) selectivity was 94%, the paraffin selectivity was 3%, and the selectivity to give higher-boiling aldehyde condensation products was 3%. Once the pressure in the reactors had been released, the discharge was treated with aqueous acetic acid solution while introducing atmospheric oxygen, until the cobalt carbonyl had been oxidized to give cobalt acetate. The aqueous, cobalt-containing phase was separated off in a phase separator, and the organic phase, as in Example 1, hydrogenated and distilled. Table III gives the composition of the C13–C15 alcohol mixture.
Reaction SMILES: C([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=O)C.[CH:22](C1N=C(NC(=O)C)SC=1)=O.Cl>C(O)(=O)C>[CH3:22][O:21][C:19](=[O:20])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][C:8]2[N:9]=[C:5]([NH2:4])[S:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CC(=O)O)cc2)cs1
Reactant: CC(=O)Nc1nc(C=O)cs1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(CCc2csc(N)n2)cc1
Temperature: 107.5 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
To {4-[2-(2-acetylamino-1,3-thiazol-4-yl)ethyl]phenyl}acetic acid (6.00 g, 19.7 mmol) that was synthesized from N-(4-formyl-1,3-thiazol-2-yl)acetamide by Wittig reaction and hydrogenation reaction based on the method described in WO2006/28269 were added acetic acid (18 ml) and concentrated hydrochloric acid (24 ml), and the mixture was heated at 105-110° C. for 5 hrs. After cooling, the reaction mixture was concentrated to dryness. 5% Hydrogen chloride methanol solution (30 ml) was added to the residue, and the mixture was stirred at 40° C. for 1.5 hrs and at room temperature for 12 hrs. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the precipitate was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give methyl{4-[2-(2-amino-1,3-thiazol-4-yl)ethyl]phenyl}acetate (5.36 g, yield 98%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]([CH3:19])([CH3:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[F:20][C:21]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH2:8][C:6]1[N:7]=[C:2]([C:27]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:20])[CH:28]=2)[CH:3]=[C:4]([NH:9][C:10]([CH3:19])([CH3:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: CC(C)(Cc1ccccc1)Nc1cc(Cl)nc(N)n1
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: C1COCCO1
Product: CC(C)(Cc1ccccc1)Nc1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 140 °C
Yield: 47.6 %

Procedure:
A mixture of 6-chloro-N4-(1,1-dimethyl-2-phenylethyl)-2,4-pyrimidinediamine (338 mg, 1.22 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (452 mg, 1.83 mmol), Pd(PPh3)4 (139 mg, 0.12 mmol) and Na2CO3 (323 mg, 3.05 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was stirred and heated at 140° C. for 30 min in a Biotage Initiator microwave synthesizer. The reaction mixture was cooled to room temperature and concentrated to dryness, and the resulting residue was partitioned between EtOAc and water. The aqueous layer was extracted by EtOAc (3×50 mL), and the combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. Purification by RPHPLC with CH3CN in water (0.01% ammonium hydrogen carbonate) (gradient: from 70% to 80% in 7.5 min, flow rate: 30 mL/min), afforded the title compound (210 mg) as a white solid. LC-MS (ES) m/z=362 [M+H]+.
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)/[CH:3]=1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1COCC1>[F:18][C:14]1[CH:13]=[C:12]2[C:17](/[C:9](=[C:4]3/[CH:3]=[C:2]([C:25]4[CH:26]=[CH:27][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=4)[C:6]([CH3:8])([CH3:7])[O:5]/3)/[C:10](=[O:19])[NH:11]2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C=O)cc1
Temperature: 65 °C
Yield: 51 %

Procedure:
To a mixture of (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (2.0 g, 6.17 mmol), 4-formyl phenylboronic acid (1.85 g, 12.3 mmol), aqueous potassium carbonate (1M, 31 mL, 31 mmol) in THF (120 mL) under a nitrogen atmosphere, was added palladium(O) tetrakis(triphenylphosphine) (356 mg, 0.3 mmol, 5 mol %). The mixture was heated at 65° C. overnight (20 h). The reaction was cooled to room temperature and ethyl acetate (500 mL) was added. The organic phase was washed with water (100 mL×2), dried over sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (5% CH3OH/CH2Cl2 elution). Trituration of the product obtained from the column chromatography with ethyl acetate/hexane (1/1), followed by isolation of the precipitate by filtration, provided 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde as a red orange solid (1.1 g, yield 51%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]N2C(=O)CCC2=O)=O)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:34][C@H:35]([C:41]([NH2:43])=[O:42])[CH2:36][CH2:37][C:38](=[O:40])[OH:39]>CN(C=O)C>[C:1]([O:5][C:6](=[O:33])[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:25])[NH:34][C@H:35]([C:41](=[O:42])[NH2:43])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:11][CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1ccc(OCCCCCCCCCC(=O)ON2C(=O)CCC2=O)cc1
Reactant: NC(=O)[C@@H](N)CCC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(OCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
4-[9-(2,5-Dioxopyrrolidin-1-yloxycarbonyl)nonyloxy]benzoic acid tert-butyl ester (200 mg, 0.433 mmol) was stirred in DMF (2 mL) and H-Glu-NH2 (63 mg) was added. The non-homogeneous mixture was stirred at rt for 16 h. LC/MS analysis indicated the reaction had not gone to completion. H-Glu-NH2 (20 mg) and more DMF (2 mL) were added and the mixture was stirred for 2 d at rt. The sample was concentrated under vacuum and AcOEt (50 mL) was added. The solution was washed with 0.2 N HCl (2×25 mL) and water (25 mL), dried over MgSO4, and concentrated under vacuum to yield a white solid (180 mg, 86% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]([CH3:38])([CH3:37])[O:29]3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:39])[CH:3]=1.[CH2:40]([S:42]([NH2:45])(=[O:44])=[O:43])[CH3:41]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:45][S:42]([CH2:40][CH3:41])(=[O:44])=[O:43])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]3([C:36]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:30]([CH3:38])([CH3:37])[O:29]3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:39])[CH:3]=1
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC3(CC2)OC(C)(C)c2ccccc23)cnc2c(C(=O)O)cnn12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC4(CC3)OC(C)(C)c3ccccc34)cnc12
Yield: 58.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-2-methylphenylamino)-6-(3,3-dimethyl-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.12 g, 0.23 mmol) obtained in step 2 and ethanesulfonamide (0.12 g, 1.17 mmol), the title compound (0.084 g, 58%) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)[CH3:18]>C(O)CO>[NH:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:30][CH:27]2[CH2:28][CH2:29][N:24]([CH2:23][C:22]3[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:20]([O:19][CH2:17][CH3:18])[CH:21]=3)[CH2:25][CH2:26]2)=[N:7][CH:6]=1
Reactant: Clc1ccc(-c2nc3ccccc3[nH]2)cn1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Solvent: OCCO
Product: CCOc1cc(CN2CCC(Nc3ccc(-c4nc5ccccc5[nH]4)cn3)CC2)ccc1OC
Yield: 9 %

Procedure:
A solution of 2-(6-chloro-pyridin-3-yl)-1H-benzoimidazole (23.0 mg, 0.10 mmol, 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.5 equiv; intermediate A1) in ethylene glycol (2 mL) was heated by microwave irradiation to 220° C. for 20 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 4.0 mg (9%) of the title compound. MS (ISP): 456.6 [M−H]−.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][C:13]1([CH3:34])[CH2:17][O:16][C:15]([C:18]2[CH:33]=[CH:32][C:21]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][CH:19]=2)=[N:14]1.[Br:35]Br.Cl>O1CCCC1>[Br:35][C:33]1[CH:32]=[C:21]([CH:20]=[CH:19][C:18]=1[C:15]1[O:16][CH2:17][C:13]([CH3:34])([CH3:12])[N:14]=1)[O:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC1(C)COC(c2ccc(OCCCN3CCCCC3)cc2)=N1
Reactant: BrBr
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccc(OCCCN3CCCCC3)cc2Br)=N1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A 2.1 M solution of n-butyllithium in hexane (580 μl, 2 eq, 1.28 mmol) is added dropwise to a solution of 1-{3-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenoxy]propyl}piperidine 1 (200 mg, 0.64 mmol, 1 eq) in cold (0° C.) tetrahydrofuran (10 ml), and the resulting solution is stirred 4 hours at 0° C. Bromine (64 μL, 2 eq, 1.28 mmol) is then added and the mixture is left to stir at 22° C. overnight. The solution is then poured into 5 ml of 0.1 N aqueous hydrogen chloride and extracted with ether. The aqueous layer is then made basic (pH 10) with 5 N sodium hydroxide and extracted with dichloromethane. The chlorinated solution is then dried over magnesium sulfate, concentrated under reduced pressure. 1-{3-[3-bromo-4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenoxy]propyl}piperidine 17 is separated from the remaining starting material by careful chromatography over silicagel (dichloromethane/methanol, gradient).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[C:16]([O:17]C)=[CH:15][C:14]([CH3:19])=[CH:13][C:12]=2[O:20]C)=[O:10])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[C:16]([OH:17])=[CH:15][C:14]([CH3:19])=[CH:13][C:12]=2[OH:20])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)c2c(OC)cc(C)cc2OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(O)c(C(=O)c2ccc(O)cc2)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
2,6-Dimethoxy-4-methylphenyl 4-methoxyphenyl ketone (321 mg) obtained in Example 45 was dissolved in anhydrous methylene chloride (10 ml), commercially available boron tribromide (349 ml) was added slowly while cooled in ice, and the admixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and then partitioned with ethyl acetate. The ethyl acetate layer was washed with brine and then dried with anhydrous magnesium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to obtain 87 mg of the title compound (yield: 68%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)[NH:9][C:8]2=[O:21].B(Br)(Br)Br.[OH-].[Na+].Cl.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[NH:9][C:8]2=[O:21]
Reactant: COc1ccc(-c2nc3c(OC)cccc3c(=O)[nH]2)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccc(O)cc2)nc2c(O)cccc12

Procedure:
8-Methoxy-2-(4'-methoxyphenyl)quinazolin-4-[3 H]-one (0.2 g, 0.71 mmol) was suspended in a 1.0 M solution of BBr3 in DCM (2.2 ml), to give a yellow suspension, which was gently refluxed for 48 hours. The solvent was directly distilled from the reaction vessel to leave a yellow/brown solid, which was hydrolysed with 10% aq. NaOH solution to give a bright yellow, clear solution. The solution was neutralised with 1.0 M aqueous HCl whereupon a cream precipitate formed, which was collected by filtration. The filtrate was extracted into EtOAc. The organic layers were combined, dried (MgSO4) and filtered. The solvent was removed under vacuum to leave a cream solid. Both products were combined (after comparison by TLC) and recrystallised from methanol (0.08 g, 0.33 mmol, 47%), m.p. 288-290° C.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:24])[C@@H:15]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:16][CH:17]=[CH2:18])C1C=CC=CC=1.[OH:25]O.O.[OH-].[Li+]>C1COCC1.O>[CH3:23][CH:21]([CH3:22])[CH2:20][CH2:19][C@@H:15]([CH2:16][CH:17]=[CH2:18])[C:14]([OH:24])=[O:25]
Reactant: OO
Reactant: C=CC[C@H](CCC(C)C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@H](CCC(C)C)C(=O)O
Reaction time: 12 h

Procedure:
To a 0° C. solution of Example 8C (17.3 g, 52.6 mmol) in THF (200 mL) was added water (25 mL) and 30% hydrogen peroxide (25 mL, 220 mmol). A solution of lithium hydroxide monohydrate (4.38 g, 104 mmol) in water (100 mL) was added and the resulting solution was stirred for 12 hours. The mixture was quenched with aqueous NaHSO3 then concentrated and made basic with 5M NaOH. The aqueous phase was washed with ethyl acetate, then acidified with concentrated HCl to pH 3 and extracted twice with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 171 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[C:12]([CH2:21][C:22]3[N:27]=[C:26]([C:28]([OH:30])=O)[CH:25]=[CH:24][CH:23]=3)=[C:11]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39].Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[C:12]([CH2:21][C:22]3[N:27]=[C:26]([C:28]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:30])[CH:25]=[CH:24][CH:23]=3)=[C:11]2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(N)(=O)=O
Reactant: COc1ccc2c(Cc3cccc(C(=O)O)n3)c(-c3ccccc3)n(S(=O)(=O)c3ccccc3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(Cc3cccc(C(=O)NS(C)(=O)=O)n3)c(-c3ccccc3)n(S(=O)(=O)c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.2 %

Procedure:
To a solution of 6-(1-benzenesulfonyl-6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylic acid (867 mg) in dichloromethane (17.4 mL) were added methanesulfonamide (199 mg), 4-dimethylaminopyridine (510 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (800 mg) successively, and this mixture was stirred at room temperature for 24 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with dichloromethane. The organic layer was washed with 1 mol/L hydrochloric acid, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: methanol-dichloromethane) to obtain the title compound (633 mg). 1H-NMR (DMSO-d6) δ ppm: 3.39 (3H, s), 3.86 (3H, s), 4.03 (2H, s), 6.85-6.98 (2H, m), 7.37 (1H, d, J=8.8 Hz), 7.39-7.53 (9H, m), 7.60-7.71 (2H, m), 7.77-7.88 (2H, m), 11.00-11.56 (1H, br). ESI-MS (m/z): 576 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([S:11]([F:14])(=[O:13])=[O:12])=[CH2:10]>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]=[CH:9][S:11]([F:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: C=CS(=O)(=O)F
Reactant: Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: O=S(=O)(F)C=CNc1ccc(Cl)cc1
Yield: 82.3 %

Procedure:
To a DMF (50 mL) solution of 4-chloroaniline (3.0 g, 23.5 mmol) was added ethenesulfonyl fluoride (3.3 mL, 30 mmol). The solution was heated at 110° C. until the 4-chloroaniline was consumed (monitored by tlc). The orange solution was diluted with 1 liter of water and the resulting oily precipitate was extracted into ether. The combined organic layers was washed with water and brine and dried (MgSO4). After the ether had been removed by distillation, the brown residue afforded the title compound (4.56 g, 81%) as yellow needles which could be crystallized from ether/hexane, mp 61°-63° C. (lit. mp 62°-63° C.; Hoechst's German Patent 1104968).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([OH:7])[CH2:3]1.C(N(CC)CC)C.[O:15]1[CH2:20][CH2:19][CH:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.CCOC(C)=O>C(Cl)Cl>[OH:7][C@H:4]1[CH2:5][CH2:6][N:2]([C:21]([CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)=[O:22])[CH2:3]1
Reactant: O=C(Cl)C1CCOCC1
Reactant: O[C@H]1CCNC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCOCC1)N1CC[C@H](O)C1
Temperature: 3 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
The (S)-pyrrolidin-3-ol hydrochloride (3.69 g, 29.9 mmol) and triethylamine (6.65 g, 9.16 mL, 65.7 mmol) were put in CH2Cl2 (15 mL). The suspension was cooled at ˜3° C. To this mixture, a solution of tetrahydro-pyran-4-carbonyl chloride (4.67 g, 29.9 mmol) in CH2Cl2 (15 mL) was added slowly. Then the resulting reaction mixture was stirred for 1.5 h at 3-10° C. The reaction mixture was then concentrated to give a powder. To this powder, addition of EtOAc (100 mL). The solid was filtered and washed with EtOAc. The recovered filtrate was then concentrated to give ((S)-3-hydroxy-pyrrolidin-1-yl)-(tetrahydro-pyran-4-yl)-methanone as beige powder. (6.77 g, 98% yield). 1H-NMR (400 MHz, Methanol-d4, 298 K): δ ppm 1.59-2.15 (m, 6H) 2.69-2.86 (m, 1H) 3.43-3.75 (m, 6H) 3.94-4.00 (m, 2H) 4.37-4.48 (m, 1H). LCMS: [M+H]+=199.9, Rt(6)=0.86 min
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[C:16]([I:17])[C:11]=3[O:10][CH:9]=2)=[CH:4][C:3]=1[O:19][CH3:20].[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:31](Cl)=[O:32]>N1C=CC=CC=1>[NH2:18][C:13]1[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:31]([C:23]4[N:22]([CH3:21])[C:30]5[C:25]([CH:24]=4)=[CH:26][CH:27]=[CH:28][CH:29]=5)=[O:32])=[C:3]([O:19][CH3:20])[CH:4]=3)=[CH:9][O:10][C:11]=2[C:16]([I:17])=[CH:15][N:14]=1
Reactant: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1N
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Solvent: c1ccncc1
Product: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
A solution of 3-(4-amino-3-methoxyphenyl)-7-iodofuro[3,2-c]pyridin-4-amine (2.53 g, 6.65 mmol) in pyridine (30 mL) was cooled to 0° C. and 1-methyl-1H-2-indolecarbonyl chloride (2.57 g, 13.3 mmol) was added. The mixture was stirred for 15 minutes at 0° C. and then allowed to rise to ambient temperature over an 18 hour time period. The solvent was removed in vacuo and the residue was dissolved in water (50 mL) and brought to pH 12 with 0.1 N aqueous sodium hydroxide, at which point a precipitate formed. The suspension was extracted with dichloromethane (4×25 mL) and the combined organic layers were washed with brine (25 mL) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title compound (3.21 g, 89%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.48 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 8.04 (t, 1H), 7.71 (d, 1H), 7.59 (d, 1H), 7.30–7.37 (m, 2H), 7.25 (d, 1H), 7.11–7.18 (m, 2H), 5.75–5.83 (bs, 2H), 4.04 (s, 3H), 3.93 (s, 3H); RP-HPLC (Conditions d) Rt 8.73 min.; MS: MH+ 539.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20][OH:21]>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:21][CH2:20][C:19]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]=3[Cl:17])[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccc(Cl)cc1Cl
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3ccc(Cl)cc3Cl)c21
Yield: 72.4 %

Procedure:
The title compound (cis/trans=25/75) was prepared as white crystals in 72.4% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=21/79) and 2,4-dichlorobenzyl alcohol.