Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[CH:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:11]12.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][C:32]([OH:34])=[O:33])=[CH:23]1.C(N(CC)CC)C>ClCCl>[CH:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([C:31]1([C:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:22]([CH3:21])[CH:23]=3)[CH2:2][C:1](=[O:5])[O:34][C:32]1=[O:33])=[C:10]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:11]12
Reactant: c1ccc2c(c1)cc1n2CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(C2(c3c4n(c5ccccc35)CCCCC4)CC(=O)OC2=O)c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 22.5 %

Procedure:
1.5 g of oxalyl chloride were added dropwise to an ice-cold solution of 2.0 g of 7,8,9,10-tetrahydro-6H-azepino[1,2-a]indole (J. Org. Chem. 33, 1968, 4286) in 50 ml of dichloromethane. The mixture was stirred for 2 hours. The solvent was removed in a vacuum and the residue was dissolved in dichloromethane. The solution obtained was added to a solution of 2.2 g of 1-methyl-3-indolylacetic acid and 2.73 g of triethylamine in 50 ml of dichloromethane. The mixture was stirred and then concentrated. The residue was chromatographed on silica gel with dichloromethane and there was obtained 1.0 g of 3-[7,8,9,10-tetrahydro-6H-azepino[1,2-a]indol-11-yl]-3-(1-methyl-3-indolyl)furan-2,5-dione of melting point 257°-259° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Br:12][CH:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=1)[CH2:14]Br>CN(C=O)C>[Br:12][CH:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=1)[CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CCc1ccc(C(Br)CBr)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(C(Br)COc2ccc(C=O)cc2)nc1
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 0.67 g (0.0055 mol) p-hydroxy benzaldehyde and 0.237 g (0.0098 mol) sodium hydride in 10 mL DMF, 1 g (0.0034 mol) 2-bromo-[5-ethyl-2-pyridyl]-ethyl bromide dissolved in 10 mL of DIVE was added at 10-15° C. Reaction mixture was stirred for 1 hr at 25-30° C. and further warmed at 75-80° C. for 24 hr. After subsequent work-up crude product was obtained which on purification gave titled compound. Yield of the product was 0.068 g (6%). The product obtained was characterized by satisfactory mass.
Reaction SMILES: [NH:1]1[C:5]2=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.P(Cl)(Cl)([Cl:13])=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>O.CCCCCC>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12
Reactant: [O-][n+]1cccc2cc[nH]c21
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: Clc1ccnc2[nH]ccc12
Temperature: 25 °C

Procedure:
A mixture of 1H-pyrrolo[2,3-b]pyridine 7-oxide (1.35 g, 10 mmol) and phosphorous oxychloride (7.6 ml) was refluxed for 6 hours. After cooling down the reaction mixture to room temperature, ice (90 ml) was added and the mixture was basified to pH 9 with a saturated aqueous solution of potassium carbonate. The brownish solid was filtered, washed with water, hexane and diethyl ether (547 mg, 3.6 mmol, 36%). LC/MS (LCT) Rt 5.74 [M+H]+ 153, 155.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][NH:20][CH2:21][CH3:22])[CH:8]=[CH:9][CH:10]=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH3:22])[CH:8]=[CH:9][CH:10]=1
Reactant: CCNCc1cccc(OC)c1-c1cccc(CC(=O)OC)c1
Reactant: O=C(Cl)OCc1ccccc1
Product: CCN(Cc1cccc(OC)c1-c1cccc(CC(=O)OC)c1)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6′-methoxy-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][CH:20]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([NH2:39])=[S:38])([CH3:29])[CH3:28].[C:40]([O-])(=[O:42])C.[Na+]>>[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([NH:39][C:40]([NH:24][CH2:23][CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[N:11]=2)[CH:16]=1)=[O:42])=[S:38])([CH3:29])[CH3:28]
Reactant: CC(=O)[O-]
Reactant: CC(C)c1ccccc1NC(N)=S
Reactant: NCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Agent: [Na+]
Product: CC(C)c1ccccc1NC(=S)NC(=O)NCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 63 using 3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (CA18) and 1-(2-isopropylphenyl)thiourea. Sodium acetate was used in place of sodium bicarbonate. The title compound was isolated as a white solid (0.131 g, 40%): 1H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 10.07 (s, 1H), 9.41 (s, 1H), 8.13-8.04 (m, 2H), 8.01-7.93 (m, 2H), 7.62 (ddd, J=7.9, 2.0, 1.0 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.41 (dd, J=7.8, 1.5 Hz, 1H), 7.39-7.32 (m, 2H), 7.27 (td, J=7.5, 1.5 Hz, 1H), 7.20 (td, J=7.5, 1.7 Hz, 1H), 7.11 (t, J=5.6 Hz, 1H), 3.18 (q, J=6.5 Hz, 2H), 3.00 (hept, J=6.8 Hz, 1H), 2.73 (t, J=7.7 Hz, 2H), 1.93-1.75 (m, 2H), 1.16 (d, J=6.9 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 583 ([M+H]+), 581 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1>C1C=CC=CC=1>[C:26]([O:13][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:7][CH2:6][C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: OCc1ccc(OCc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc(OCc2ccc(Cl)cc2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 1.2g of 4-(4'-chlorobenzyloxy)benzyl alcohol, 1.0g of triethylamine and 25 ml of anhydrous benzene was added 0.9g of hydrochloride of nicotinoyl chloride at 10° C. The whole mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water. The organic layer was dried over sodium sulfate and then concentrated in vacuo to give a crystalline residue. The residue was recrystallized from ethanol to give 1.2g of 4-(4'-chlorobenzyloxy)benzyl nicotinate, mp 101°-2° C.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:24]=[N:25][C:26](Cl)=[CH:27][C:28]=2[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[C:18]([C:36]#[N:37])[CH:17]=1)(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)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>[C:36]([C:18]1[CH:17]=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:15])=[O:14])[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:24]=[N:25][C:26]([C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=2)=[CH:27][C:28]=1[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)#[N:37]
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1ccc(Oc2cnc(Cl)cc2-c2cccnc2)c(C#N)c1
Reactant: OB(O)c1cccc(F)c1
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: CN(C)C=O
Product: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1cnc(-c2cccc(F)c2)cc1-c1cccnc1
Reaction time: 0.08 h
Yield: 31.5 %

Procedure:
10 mg (0.03 mmol) of tert-butyl((4-((6′-chloro-[3,4′-bipyridin]-3′-yl)oxy)-3-cyanophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 3.7 mg (0.03 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 2 mg (10 mol %) of Pd(PPh3)4, 5.6 mg (0.05 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 5 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)[Cl:23].C([O-])(O)=O.[Na+].C(Cl)Cl>C(O)C>[OH2:26].[Cl:23][CH2:22][CH:24]([OH:26])[CH2:25][N:19]1[CH2:18][CH2:17][N:16]([CH:8]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:21][CH2:20]1
Reactant: ClCC1CO1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: O
Product: OC(CCl)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 100.8 %

Procedure:
[Bis(4-fluorophenyl)methyl]piperazine, (14.4 g, 0.05 mol) in ethanol (200 mL) was added dropwise to epichlorohydrin (3.5 mL, 0.05 mol) in ethanol (12 mL) at 0° C. with NaHCO3 anhydrous (4.2 g, 0.05 mol) over 45 min under N2. The ice bath was removed and the mixture was allowed to come to room temperature. After 18 h the NaHCO3 was removed by filtration via a sintered glass funnel and the ethanol in the filtrate was removed in vacuo to give the crude product (21.3 g). Flash chromatography over silica gel using 2.0% methanol: methylene chloride gave pure product (10.05 g, 52.9%) as an amber oil. DCI/MS (M+1) 381. 400 MHz 1H NMR (CDCl3) δ: 7.3 (m, 4H), 6.95 (m, 4H), 4.2 (s, 1H), 3.95 (m, 1H), 3.55 (m, 2 H), 2.7 (m, 2H), 2.5 (m, 4H), 2.4 (m, 4H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([C:14]1[CH:22]=[C:21]3[C:17]([CH:18]=[CH:19][N:20]3[CH2:23][C:24]([O:26]CC)=[O:25])=[CH:16][CH:15]=1)[CH2:9]2>O.C1COCC1.CO>[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([C:14]1[CH:22]=[C:21]3[C:17]([CH:18]=[CH:19][N:20]3[CH2:23][C:24]([OH:26])=[O:25])=[CH:16][CH:15]=1)[CH2:9]2
Reactant: CCOC(=O)Cn1ccc2ccc(N3Cc4cccc(C)c4C3=O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc2c1C(=O)N(c1ccc3ccn(CC(=O)O)c3c1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NaOH (1.86 mmol, 1.3 equiv.), dissolved in water (6 ml), was added to a solution of ethyl 2-(6-(7-methyl-1-oxoisoindolin-2-yl)-1H-indol-1-yl)acetate (1.44 mmol, 1 equiv.) in THF/MeOH (1:1, 5 ml), and the mixture was stirred for 2 h at 25° C. The reaction solution was concentrated under reduced pressure, and the aqueous residue was adjusted to pH 3 with 1 M HCl and extracted with ethyl acetate (3×50 ml). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. Yield: quantitative
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].O1CCCC1.[F:16][C:17]1[CH:35]=[CH:34][C:20]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1>CC1C=CC=CC=1.C(O)(=O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:22])([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:28]2)=[CH:34][CH:35]=1
Reactant: CCOC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: COc1ccc(Br)cc1
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(OC)cc2)CC1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a stirred and refluxing Grignard complex previously prepared starting from 112.2 parts of 1-bromo-4-methoxybenzene, 15 parts of magnesium and 540 parts of tetrahydrofuran was added dropwise a solution of 84 parts of ethyl 4-(4-fluorobenzoyl)-1-piperidinecarboxylate in 360 parts of tetrahydrofuran. Upon completion, stirring was continued for 2 hours at reflux. After cooling to 10° C., the reaction mixture was poured onto a mixture of 300 parts of crushed ice and 40 parts of acetic acid. The whole was stirred for 5 minutes. 360 Parts of methylbenzene were added. The organic layer was separated, dried, filtered and evaporated, yielding 100 parts of ethyl 4-[(4-fluorophenyl)hydroxy(4-methoxyphenyl)-methyl]-1-piperidinecarboxylate as an oily residue (intermediate 10).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:19][O:20][CH3:21])[C:13]=2[CH:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][NH:43][CH3:44].[C:45](=[O:47])=O>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:42][N:43]([CH3:44])[C:45]([C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:19][O:20][CH3:21])[C:13]=2[CH:12]=1)=[O:47]
Reactant: O=C=O
Reactant: COCn1c(C)nc2c(OCc3ccccc3)c(Br)ccc21
Reactant: CNC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCn1c(C)nc2c(OCc3ccccc3)cc(C(=O)N(C)C)cc21
Yield: 50 %

Procedure:
10.6 g (29.3 mmol) 4-Benzyloxy-bromo-1-methoxymethyl-2-methyl-1H-benzimidazole, 4.6 g (17.6 mmol) triphenylphosphine, 1.0 g (4.3 mmol) palladium(II) acetate, 148 ml (293 mmol) dimethylamine (2 M in THF) in 50 ml tetrahydrofuran were transferred to an autoclave and carbonylated (6 bar CO2) at 120° C. for 16 h. The catalyst was filtered off and the filtrate was concentrated in vacuo. The purification of the residue by column chromatography on silica gel (dichloromethane/methanol=20:1) afforded 4.9 g (50%) of the title compound as a yellow oil.
Reaction SMILES: O=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH3:11][O:12][CH2:13][CH2:14][CH2:15][NH2:16].[Cl:17][CH2:18][CH2:19][N:20]=[C:21]=[O:22]>>[Cl:17][CH2:18][CH2:19][NH:20][C:21]([N:16]([CH2:15][CH2:14][CH2:13][O:12][CH3:11])[CH:9]1[O:10][CH2:2][C@@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])=[O:22]
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: COCCCN
Reactant: O=C=NCCCl
Product: COCCCN(C(=O)NCCCl)C1OC[C@@H](O)[C@@H](O)[C@@H]1O
Yield: 76.6 %

Procedure:
3.0 g of D-arabinose, 3.6 g of 3-methoxy-n-propyl-amine and 3.0 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 13-(1). 5.0 g of 1-(2-chloroethyl)-3-(3-methoxy-n-propyl)-3-(D-arabinopyranosyl)-urea are thereby obtained as colorless caramel.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)=[O:22])=[O:10])[CH2:5][CH2:4]1.[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][CH:41]=O)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][N:2]([C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)=[O:22])=[O:10])[CH2:7][CH2:8]1)[CH3:1])=[O:37])([CH3:32])([CH3:33])[CH3:34]
Reactant: CN[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Reactant: CC(C)(C)OC(=O)NCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCCNC(=O)OC(C)(C)C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1

Procedure:
Trans-3-[4-(methylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (250 mg) obtained in Example 221 is suspended in dichloromethane (8 ml), and thereto are added 3-t-butoxycarbonylaminopropanal (198 mg) and triethylamine (160 μl) under ice-cooling, and the mixture is stirred for several minutes. Then, sodium triacetoxy borohydride (243 mg) and the reaction solution is warmed to room temperature, and stirred for 4 hours. To the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture is extracted with chloroform. The organic layer is washed successively with water and a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1, then 1/1) to give the title compound (312 mg).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([F:19])[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.ClC1C=C(C2[NH:28][C:29](=[S:39])NC=2C2C=CC(F)=CC=2)C=CN=1>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[NH:28][C:29](=[S:39])[NH:2][C:3]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([F:19])[CH:14]=2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccnc(Cl)c2)cc1
Reactant: NC(C(=O)c1ccc(F)cc1)c1ccnc(F)c1
Agent: Cl
Product: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccnc(F)c2)cc1

Procedure:
24b was prepared from 23b (6.1 g; 20 mmol) using the method described in the synthesis of 24a.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=O.Cl.[NH2:15][OH:16].O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[N:15][OH:16]
Reactant: NO
Reactant: Cc1cc(C)c2c(c1)C(=O)CCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2c(c1)C(=NO)CCC2
Temperature: 80 °C
Yield: 93.9 %

Procedure:
A solution of 5,7-Dimethyl-1-tetralone (5.0 g) in ethanol (100 mL) was treated with hydroxylamine hydrochloride (2.2 g) and sodium carbonate monohydrate (3.6 g). The reaction mixture was heated overnight at 80° C. with a condenser and behind a blast shield. Cooled to room temperature after seventeen hours, transferred to a 300 mL flask and concentrated. The residue was triturated in water and filtered to yield the title product as a beige solid (5.1 g).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:15])[C:4]=2[CH:3]=1.[N:16]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[C@@H:18](O)[CH2:17]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:16]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[C@H:18]([O:1][C:2]1[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5](=[O:15])[C:4]=3[CH:3]=1)[CH2:17]2
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Reactant: O[C@H]1CN2CCC1CC2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2-c2ccc(O[C@@H]3CN4CCC3CC4)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a 0° C. mixture of 2-hydroxyfluoren-9-one (196 mg, 1.00 mmol; Aldrich), (3R)-quinuclidin-3-ol (151 mg, 1.20 mmol; Acros), and polymer-bound triphenylphosphine (500 mg, 3 mmol/g; Aldrich) in THF (5 mL) was added diethylazodicarboxylate (200 μL, 1.27 mmol; Aldrich). After 1 h, the reaction mixture was allowed to warm to room temperature and was stirred overnight (16 h). The mixture was filtered through diatomaceous earth, the filter pad rinsed with dichloromethane, and the organic extracts purified twice by flash chromatography (80 g silica gel, eluting with 1-5% of 10% NH4OH/MeOH in CH2Cl2) to afford the title compound (104 mg, 0.340 mmol, 34% yield). MS (DCI/NH3): m/z 306 (M+1)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:19](Cl)=[O:20])[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.Cl.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26].C(N(CC)CC)C>ClCCl>[F:23][C:24]([F:28])([F:27])[CH2:25][NH:26][C:19]([C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:20]
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
23 g (0.063 mol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride are added dropwise at 0° C. under nitrogen to a solution of 9.35 g (0.069 mol) of 2,2,2-trifluoroethylamine-hydrochloride and 26 ml (0.188 mol) of triethylamine in 550 ml of dichloromethane and stirred for 2 hours at ambient temperature. The reaction mixture is extracted twice with water, 1N hydrochloric acid and sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate and the solvent is distilled off. Purification is by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=8:1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N+:19]([O-])=[CH:18][C:17]=3[N:27]=[C:14]2[CH2:13][O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:28].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[C:18]([NH2:28])[C:17]=3[N:27]=[C:14]2[CH2:13][O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][n+]1cc2nc3n(c2c2ccccc21)[C@@H](COCc1ccccc1)COC3
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc1n2[C@@H](COCc2ccccc2)COC1
Reaction time: 2.5 h

Procedure:
(11S)-11-[(benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (0.96 g, 2.67 mmol) was dissolved in 25 mL of CH2Cl2 and treated with 2.5 mL of concentrated aqueous NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (0.51 g, 2.67 mmol) was carefully added. Rapid stirring was continued for 2.5 hours. The reaction mixture was then treated with 50 mL of CH2Cl2 and 25 mL of H2O. The layers were separated and the organic portion was washed successively with 5% Na2CO3 solution (3×25 mL), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 15-25% CMA/CHCl3) gave a light-brown foam. Crystallization from ethyl acetate and a small amount of methanol gave (11S)-11-[(benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (420 mg) fine white needles, mp 184.6-186.2° C.
Reaction SMILES: [Br:1][CH2:2][C:3]#[C:4][CH2:5][CH3:6].[N:7]12[CH2:14][CH2:13][CH:10]([CH2:11][CH2:12]1)[C@@H:9]([O:15][C:16](=[O:29])[C:17]([OH:28])([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[CH2:8]2>C(Cl)(Cl)Cl>[Br-:1].[OH:28][C:17]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[C:16]([O:15][C@@H:9]1[CH:10]2[CH2:13][CH2:14][N+:7]([CH2:2][C:3]#[C:4][CH2:5][CH3:6])([CH2:12][CH2:11]2)[CH2:8]1)=[O:29]
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1cccs1)c1cccs1
Reactant: CCC#CCBr
Solvent: ClC(Cl)Cl
Product: CCC#CC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2
Product: [Br-]
Temperature: 50 °C

Procedure:
A solution of 1-bromo-2-pentyne (0.51 g, 3.44 mmol) in chloroform (2 ml) is treated with polymer supported TEA resin. After a few minutes this solution is added to a solution of hydroxy-di-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo-[2.2.2]oct-3-yl) ester (Example 70(ii)) (1.0 g, 2.87 mmol) in chloroform (2 ml). The resulting mixture is heated to 50° C. for 18 h and the mixture allowed to cool to room temperature. A white solid is isolated by filtration, washed with chloroform and dried. Recrystallisation from chloroform-acetonitrile, washing the resultant solid with cold acetonitrile, and drying under vacuum gives (R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-pent-2-ynyl-1-azonia-bicyclo[2.2.2]octane bromide.