Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:5][C@H:6]1[O:8][CH2:7]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[C:24]12([CH2:34][NH:35][C:36](=[O:45])[C:37]3[C:42]([Br:43])=[CH:41][N:40]=[C:39]([OH:44])[CH:38]=3)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>CN(C)C=O.O>[C:24]12([CH2:34][NH:35][C:36](=[O:45])[C:37]3[C:42]([Br:43])=[CH:41][N:40]=[C:39]([O:44][CH2:5][C@@H:6]4[CH2:7][O:8]4)[CH:38]=3)[CH2:31][CH:30]3[CH2:32][CH:26]([CH2:27][CH:28]([CH2:29]3)[CH2:33]1)[CH2:25]2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(O)ncc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OC[C@@H]2CO2)ncc1Br
Temperature: 60 °C
Yield: 25.5 %

Procedure:
A suspension of (S)-glycidyl nosylate (0.29 g), caesium carbonate (1.82 g) and N-(1-adamantylmethyl)-5-bromo-2hydroxyisonicotinamide (0.41 g) (Example 35(ii)) in anhydrous N,N-dimethylformamide (6 ml) was heated at 60° C. under nitrogen for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted with water (50 ml) and extracted into ethyl acetate (3×20 ml). The combined extracts were dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with dichloromethane:ethyl acetate (4:1 to 0:1) to afford the sub-titled compound (0.12 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([N:12]([CH3:14])[CH3:13])[N:6]=1)(=O)[CH3:2].Cl.[CH3:16][N:17](C)[CH2:18]CCl>>[CH3:16][N:17]([CH3:18])[CH2:2][CH2:1][NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([N:12]([CH3:14])[CH3:13])[N:6]=1
Reactant: CC(=O)Nc1nc(C)cc(N(C)C)n1
Reactant: CN(C)CCCl
Agent: Cl
Product: Cc1cc(N(C)C)nc(NCCN(C)C)n1

Procedure:
Following the procedure of Example 1, Part A 2-acetamido-4-methyl-6-dimethylaminopyrimidine and 2-dimethylaminoethyl chloride hydrochloride, 2-(2-dimethylaminoethylamino)-4-methyl-6-dimethylaminopyrimidine is obtained with a boiling point of 120°-124° C. at 0.03 mm.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:27])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([NH2:25])[C:9]1=[O:26])([CH3:4])([CH3:3])[CH3:2].[C:28]1([CH3:37])[CH:33]=[CH:32][CH:31]=[C:30]([N:34]=[C:35]=[O:36])[CH:29]=1>C(Cl)Cl>[C:1]([NH:5][C:6](=[O:27])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([NH:25][C:35]([NH:34][C:30]2[CH:29]=[C:28]([CH3:37])[CH:33]=[CH:32][CH:31]=2)=[O:36])[C:9]1=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)CN1C(=O)C(N)CC(c2ccccc2)c2ccccc21
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)NC2CC(c3ccccc3)c3ccccc3N(CC(=O)NC(C)(C)C)C2=O)c1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a 25 ml round-bottomed flask equipped with N2 inlet were added N-tert-butyl-2-[3-amino-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoic acid amide (0.50 g, 1.368 mmoles) and 10 ml methylene chloride under nitrogen, and the reaction cooled in an ice bath. A solution of m-tolyl isocyanate (0.194 ml, 1.5 mmol) in 5 ml methylene chloride was then added dropwise. A solid formed immediately. Stirring was continued for 15 minutes and then the ice bath removed, allowing the reaction to come to room temperature for several hours. The solid was filtered and washed with methylene chloride/hexane (1:1), yielding 600 mg (87.9%) of product, mp 263°-266° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([C:10]([O:12]CC)=[O:11])=[N:4]1)[CH3:2].[OH-].[Na+].C(OCC)(=O)C.O>C(O)C>[CH2:1]([N:3]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([C:10]([OH:12])=[O:11])=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)n(CC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCc1cc(C(=O)O)nn1CC
Reaction time: 8 h
Yield: 82.8 %

Procedure:
Ethyl 1,5-diethylpyrazole-3-carboxylate (20.7 g) in ethanol (250 ml) was treated with 2.5M aqueous NaOH (50.6 ml), and the mixture was stirred overnight. A further 4.2 ml of 2.5M NaOH was then added and stirring continued for a further 1 hour. The mixture was then poured into ethyl acetate/water. The mixture was shaken vigorously and the aqueous phase removed. The pH of the aqueous phase was adjusted to 2.0 using 1M aqueous HCl and saturated with NaCl. The aqueous layer was then extracted with 20% toluene/80% THF (5×100 ml). The combined organic extracts were dried over MgSO4 and evaporated in vacuo. The residue was triturated with hexane/diethyl ether to give the acid as a solid (14.69 g); υmax(CH2Cl2) 3450, 2750, 2596, 1697, cm−1; δ(CDCl3) 1.31 (3H, t, J 7 Hz), 1.44 (3H, t,J 7 Hz) 2.64 (2H, q, J 7 Hz), 4.20 (2H, q, J 7 Hz), 6.64 (1H,s) ppm.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=1[CH3:11].C(OC)(=O)[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[K+]>CCOC(C)=O.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:3]([CH3:11])[C:4]=1[F:10])#[N:7]
Reactant: COC(=O)CC(=O)OC
Reactant: Cc1c(Br)ccc(C#N)c1F
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C#N)c(F)c1C
Temperature: 170 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
Combine 4-bromo-2-fluoro-3-methylbenzonitrile (2 g, 9.34 mmol), dimethyl malonate (12.28 mL, 107 mmol), potassium carbonate (1.937 g, 14.02 mmol) and potassium hydrogencarbonate (1.403 g, 14.02 mmol). Nitrogen gas was bubbled through this mixture vigorously for 1 minute and then tri-tert-butylphosphonium tetrafluoroborate (0.030 g, 0.103 mmol), and bis(dibenzylidineacetone)palladium (0) (0.027 g, 0.047 mmol) were added. The reaction mixture was then heated in an oil bath (170° C.) and stirred for 1 hour, then cooled to ambient temperature and diluted with EtOAc (80 mL). The EtOAc layer was decanted and passed through a plug of Celite® (˜7 cm wide and 1.5 cm thick). The chunky dark precipitate that was left in the flask was diluted with additional EtOAc portions and sonicated until a fine suspension resulted. The EtOAc triturates were also passed through the Celite® plug. The combined organics from filtration were concentrated in vacuo at ˜40° C. and then at 90° C. for 45 minutes to give a residue. The residue was purified using flash column chromatography to give the title compound (1.05 g, 5.07 mmol, 54.2%) as a clear colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.17 (d, J=2.27 Hz, 3 H) 3.63 (s, 3 H) 3.91 (s, 2 H) 7.29 (d, J=8.08 Hz, 1 H) 7.71 (t, J=7.33 Hz, 1 H)
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH2:15][CH2:14][CH2:13][C@H:10]1[CH2:11][OH:12])=[O:8].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1>C(#N)C.C1(C)C(S(O)(=O)=O)=CC=CC=1.N1C=CC=CC=1>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH2:15][CH2:14][CH2:13][C@H:10]1[CH2:11][O:12][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][O:16]1)=[O:8]
Reactant: O=C1CC[C@@H](C(=O)N2CCC[C@H]2CO)N1
Reactant: C1=COCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C1CC[C@@H](C(=O)N2CCC[C@H]2COC2CCCCO2)N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 109.9 %

Procedure:
The thus obtained L-pyroglutamyl-L-prolinol (110 g, 0.519 mol) and dihydropyran (220 g, 2.62 mol) are dissolved in acetonitrile (2.75 l), and pyridine toluenesulfonate (11 g) is added under water-cooling. The mixture is stirred at room temperature for two days, and the reaction liquid is concentrated under reduced pressure, dissolved again in methylene chloride (1.5 l) and washed successively with 5% potassium carbonate (1 l) and water (1 l). The methylene chloride layer is dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated to dryness under reduced pressure to give N-pyroglutamyl-O-tetrahydropyranyl-L-prolinol (169 g, 110%).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11](S(C4C=CC=CC=4)(=O)=O)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.F[B-](F)(F)F.[O:29]=[N+:30]=[O:31].[OH-].[K+].Cl>ClCCCl.C(Cl)Cl.O>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[NH:11][C:8]=3[CH:9]=[C:10]([N+:30]([O-:31])=[O:29])[C:5]2=[N:4][N:3]=1
Reactant: O=[N+]=O
Reactant: Cc1cc2c(ccc3nnc(C)n32)n1S(=O)(=O)c1ccccc1
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: Cc1cc2c(cc([N+](=O)[O-])c3nnc(C)n32)[nH]1
Reaction time: 8 h

Procedure:
To a solution of 1,7-dimethyl-6-(phenylsulfonyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (1.0 g, 3.1 mmol, from Example 228, Step 4) in 1,2-dichloroethane (20 mL) was added nitronium tetrafluoroborate (0.57 g, 4.3 mmol, Aldrich). The reaction mixture was stirred overnight, filtered and washed with DCE, and air-dried overnight. To a suspension of the nitrated product in Methanol (7 mL) was added 10% (w/w) KOH in water (7 mL, 10 mmol) and the reaction mixture was stirred for 3 hours, after which time the reaction mixture was diluted with DCM and water. 2.0 M solution of HCl in water (4.0 mL, 8.0 mmol) was added to adjust pH 10 and the mixture was stirred for 2 hours. The precipitated solid was isolated by filtration, washed with DCM and water, and then dried at 50° C. under high vacuum for 2 hours. Yield: (0.30 g, 40%).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH2:27])([CH3:24])[CH3:23].[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](O)=[O:44]>CN(C=O)C>[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([NH:27][C:26]1[C:25]([CH:22]([CH3:24])[CH3:23])=[CH:31][CH:30]=[CH:29][C:28]=1[CH:32]([CH3:34])[CH3:33])=[O:44]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)CCCCCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCCCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.7 %

Procedure:
WSC (1.05 g, 5.5 mmols) and HOBt (743 g, 5.5 mmols) were added to a DMF (15 ml) solution of 2,6-diisoproylaniline (886 g, 5 mmols) and 8-bromooctanoic acid (1.67 g, 7.5 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 720 mg (yield: 38%) of 8-bromo-N-(2,6-diisopropylphenyl)octanamide as colorless needle-like crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1(=[O:20])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C1C=CC=CC=1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:13]2=[O:20])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCCCCN1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C1NCCCCC1C(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 94.6 %

Procedure:
A mixture of 4-nitrobenzoyl chloride (50.16 g, 0.27 mol), freshly distilled ε-caprolactam (30.59 g, 0.27 mol), and 500 ml of benzene are added to a 1L three-necked round-bottom flask equipped with an overhead stirrer, condenser and a nitrogen inlet tube. The solution is heated to 90°-100° C. and after all the solids are dissolved, 160 ml of pyridine is added. White pyridine salts form immediately, the reaction solution being kept at 90°-100° C. for 1 hour. The pyridine salts are removed by filtration, and the solvent is separated from the filtrate under reduced pressure. The residue is washed with a 5 percent NaHCO3 aqueous solution and with distilled water several times before being dried. The product is then recrystallized from a mixture of ethyl acetate and hexane to obtain 67 g (95 percent) of white crystals: mp 105°-106° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][O:54][C:55]1[CH:56]=[C:57]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([NH2:69])[CH:64]=2)[CH:58]=[CH:59][C:60]=1[O:61][CH3:62]>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:56]=[C:57]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([NH:69][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:64]=2)[CH:58]=[CH:59][C:60]=1[O:61][CH3:62]
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: COc1ccc(-c2cccc(N)c2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)cc1OC
Temperature: 25 °C
Yield: 66.6 %

Procedure:
DIEA (0.0144 mL, 0.072 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.018 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3′,4′-Dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.021 g of product in 65% yield: LCMS (ESI) m/z 486 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.Cl.[NH2:13]O.[Na+].C([O-])(=O)C>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:13]
Reactant: COc1ccc(C=O)cc1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C#N)cc1O

Procedure:
First, a mixture of 3-hydroxy-4-methoxy benzaldehyde (25 g, 164.3 mmol), hydroxylamine hydrochloride (13.7 g, 197.2 mmol), and acetic acid sodium salt (27 g, 328.6 mmol) in acetic acid (200 ml) was refluxed overnight. After cooling, the acetic acid was evaporated under reduced pressure. Water was added to the residue and the resulting precipitate was collected by filtration. The crude product was recrystalized to give 3-hydroxy-4-methoxy benzonitrile. (23.54 g, 96%)
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.[BH4-].[Na+].ClCCl>C(O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]([NH:16][CH2:17][CH2:18][CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NCCCn1ccnc1
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: Clc1ccc(C(NCCCn2ccnc2)c2ccccc2)cc1
Temperature: 130 °C

Procedure:
In a similar manner to Example 1, a mixture of 4-chlorobenzophenone (8.0 g) and 1-(3-aminopropyl)imidazole (4.6 g) was heated at 130° C. for 12 hours. The mixture was cooled, dissolved in absolute ethanol (100 ml), treated with sodium borohydride (2.8 g) and the mixture boiled under reflux for 8 hours. The oil obtained after work-up, using dichloromethane as the extracting solvent, was distilled to give N-[α-(4-chlorophenyl)benzyl]-3-(imidazol-1-yl)propylamine, b.p. 240° C. (0.3 mmHg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])CCC.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.II.[OH-].[Na+]>CCOCC.CCCCCC.O1CCCC1.O>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=2)[N:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: Fc1ccc(Br)cc1
Reactant: Clc1ccc2nccc(Cl)c2c1
Agent: II
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: Fc1ccc(-c2cc(Cl)c3cc(Cl)ccc3n2)cc1
Reaction time: 0.25 h
Yield: 48.8 %

Procedure:
To a solution of 5.5 ml (50 mmol) of 1-bromo-4-fluorobenzene in 70 ml of ether cooled to -40° was added 21 ml of a 2.4M solution of butyl lithium in hexane while maintaining the temperature below -15°. This mixture was stirred at -15° for 15 min. A solution of 7.42 g (40 mmol) of 4,6-dichloroquinoline in 40 ml of tetrahydrofuran was added while maintaining the temperature at -20°. It was allowed to warm to 0° during 15 min. To the reaction mixture was then added 10 ml of water and 10.16 g (40 mmol) of iodine, and 15 ml of 3N sodium hydroxide. After 10 min of stirring this mixture was then cooled to 5°, and the solid collected. This solid was dissolved in methylene chloride, and the solution filtered through a plug of alumina. The filtrate was concentrated in vacuo to leave a residue which was crystallized from ethyl acetate to give 5.7g of crude product, mp 150°-156°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](S(C3C=CC=CC=3)=O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1([Mg]Cl)C=CC=CC=1.[N+:29]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH:36]([C:35]3[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:39][CH:38]=3)[OH:37])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(S(=O)c3ccccc3)ccnc2c1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2c(C(O)c3ccc([N+](=O)[O-])cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-methoxy-4-(phenylsulfinyl)quinoline (0.232 g, 0.819 mmol) in THF (6 mL) at −78° C. was added phenylmagnesium chloride (2.0 M in THF)(0.819 ml, 1.64 mmol). After 5 min, the solution was warmed to RT for 15 minutes. The solution was then cooled to −78° C. and 4-nitrobenzaldehyde (0.371 g, 2.46 mmol) was added in one portion. After 5 min, the solution was warmed to RT. After 1 hr at RT, the reaction was quenched with saturated NH4Cl. The mixture was diluted with CH2Cl2 and washed with water and brine. The organic fraction was dried with Na2SO4 and concentrated in vacuo. The yellow residue was purified by silica gel chromatography using 20-100% Hexanes:EtOAc to afford (7-methoxyquinolin-4-yl)(4-nitrophenyl)methanol as a white solid. MH+=311.2@1.44 min
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][CH2:11][CH2:12][N:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:22]([O:24]C)=[O:23])[CH:15]=[N:14]3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.O.[OH-].[Li+:28]>O1CCCC1.O>[N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][CH2:11][CH2:12][N:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:22]([O-:24])=[O:23])[CH:15]=[N:14]3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Li+:28]
Reactant: COC(=O)c1cccc2cnn(CCNCC34CCN(CC3)CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cccc2cnn(CCNCC34CCN(CC3)CC4)c12
Yield: 211.1 %

Procedure:
A mixture of methyl 1-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indazole-7-carboxylate (563 mg, 1.7 mmol) from Step F above and lithium hydroxide monohydrate (207 mg, 4.9 mmol) in tetrahydrofuran/water (16 mL; 1:1) was stirred at reflux until the reaction was complete by TLC and/or LC-MS. The solvent was removed under reduced pressure to give lithium 1-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indazole-7-carboxylate (1.20 g, crude): 1H NMR (300 MHz, CD3OD) δ 8.03 (s, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.55 (d, J=7.2 Hz, 1H), 7.11 (t, J=7.4 Hz, 1H), 3.28-3.20 (m, 2H), 2.98 (t, J=6.6 Hz, 2H), 2.81 (t, J=7.5 Hz, 6H), 2.28 (s, 2H), 1.36 (t, J=8.1 Hz, 6H).
Reaction SMILES: C(C[CH2:4][CH:5]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1)#N.S(=O)(=O)(O)O.[C:20]([OH:23])(=[O:22])[CH3:21]>O>[O:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6][CH:5]1[CH2:4][CH2:21][C:20]([OH:23])=[O:22]
Reactant: N#CCCC1COc2ccccc2O1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CCC1COc2ccccc2O1

Procedure:
72 g 2-(2-cyanoethyl) (2,3-dihydro [4H] 1,4-benzodioxin) are suspended in 100 ml acetic acid, 100 ml water and 40 g sulphuric acid. The whole is heated to reflux for 48 hours and the mixture is thereafter poured in water. The aqueous phase is extracted with ether. The ethereous solution is separated, washed, dried and concentrated off. 76 g of 3-(2,3-dihydro [4H] 1,4-benzodioxin-2 yl) propionic acid are obtained, melting at 102°. This acid is esterified with methanol and p toluene sulphonic acid at the boiling point for 18 hours. After the usual purifications 71 g of the methyl ester are obtained. MP: 55°.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:12][C:13]3[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=3)[C:5]=2[CH2:4][CH2:3]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1.O1CCCC1.CN(C)C=O>O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:17][C:16]2[CH:15]=[CH:14][C:13]([O:12][C:6]3[C:5]4[CH2:4][CH2:3][C:2](=[O:1])[NH:11][C:10]=4[N:9]=[CH:8][CH:7]=3)=[CH:19][CH:18]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: Nc1ccc(Oc2ccnc3c2CCC(=O)N3)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2N1

Procedure:
4-[(7-Oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-4-yl)oxy]aniline (43 mg), p-fluorophenyl isocyanate (28 mg), tetrahydrofuran (5 ml) and dimethylformamide (2 ml) were stirred at room temperature for 30 minutes. Water was added dropwise at room temperature until precipitation of crystals, and these were filtered out to obtain 48 mg of the target substance as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14]CC)=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18]C(C)C)[CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([OH:14])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC(C)C)cc(Cl)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1OB(O)c2cc(O)cc(Cl)c21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 2-(4-chloro-1-hydroxy-6-isopropoxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (200 mg, 0.74 mmol) in 10 mL THF was added LiOH (100 mg, 2.22 mmol) in 5 mL H2O dropwise at 0° C. The mixture was stirred at room temperature for 1.5 h and acidified to pH=5.0 using 1N HCl (8 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was use directly in next step reaction without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.[H-].[Na+].[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][CH2:22][C:21](=O)[C:20]=2[CH:25]=1.O>C1COCC1>[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([CH2:4][C:3]([N:2]([CH3:1])[CH3:12])=[O:11])=[CH:21][C:20]=2[CH:25]=1
Reactant: COP(=O)(CC(=O)N(C)C)OC
Reactant: O=C1COc2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1cc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethyl [2-(dimethylamino)-2-oxoethyl]phosphonate (5 g) was added to a stirred suspension of sodium hydride (1.02 g of a 60% dispersion in oil) in dry THF (100 ml) at 0° under nitrogen. After stirring for 15 minutes 5-bromo-3-(2H)-benzofuranone (5.0 g) in THF (20 ml) was added dropwise and stirred at room temperature for 3 h. Water (50 ml) was added and the mixture extracted with ethyl acetate (3×50 ml), dried and the solvent removed in vacuo. The crude material was purified by flash chromatography using 50% ethyl acetate/hexane as eluant to yield the title compound as a pale yellow solid m.p. 92°-94° C.