Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([NH:15]C(OCC3C=CC=CC=3)=O)=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:26])=[O:4].[H][H]>CO.C1COCC1.[C].[Pd]>[CH3:1][N:2]([CH3:27])[C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([NH2:15])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:26])=[O:4]
Reactant: CN(C)C(=O)C1Cc2ccc(NC(=O)OCc3ccccc3)cc2NC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)C1Cc2ccc(N)cc2NC1=O
Yield: 92.2 %

Procedure:
To a suspension of N,N-dimethyl-7-benzyloxycarbonylamino-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxamide (820 mg) in methanol (8 ml) and THF (8 ml) was added 10% palladium-carbon (100 mg). The reaction mixture was stirred under one atmospheric pressure of hydrogen at room temperature for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated. The precipitated crystals were washed with combined solution of IPE and THF to obtain the entitled compound (480 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:26]4[CH:27]=[CH:28][S:24][CH:25]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: OB(O)c1ccsc1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4ccsc4)c(C(=O)O)s3)c2cc1OC
Yield: 77.7 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and thiophene-3-boronic acid (19.2 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-thiophen-3-yl-thiazole-5-carboxylic acid (30.1 mg, 78%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.74 (br.s., 1 H); 8.84 (s, 1 H); 8.55 (dd, 1 H); 7.91 (dd, 1 H); 7.86 (s, 1 H); 7.66 (dd, 1 H); 7.40 (s, 1 H); 3.891 (s, 3 H); 3.85 (s, 3 H)═. MS m/z 388 (M+1).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[N+](C1C=CC=CC=1)([O-])=O.S(Cl)(Cl)=O.[CH3:23][C:24]1[CH:32]=[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]2[N:25]=1>Cl>[CH3:23][C:24]1[C:32]([C:1](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)=[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]2[N:25]=1
Reactant: Cc1cc2ccccn2n1
Reactant: O=C(O)c1cccnc1
Agent: Cl
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1nn2ccccc2c1C(=O)c1cccnc1
Temperature: 0 °C

Procedure:
To a mixture of 107 g of nicotinic acid and 315 ml of nitrobenzene were added dropwise whilst stirring 107 g of thionyl chloride, the mixture was warmed for one hour at a temperature of 160°-180° C. The reaction mixture was allowed to cool, then 35 g of 2-methylpyrazolo[1,5-a]pyridine was introduced in one portion, and the mixture was heated to 140°-160° C. for 2 hours, and poured into 1 l of ice water. Next, 50 ml of concentrated hydrochloric acid were added. This solution was extracted twice with 500 ml of benzene. After neutralizing with potassium carbonate, the aqueous layer was extracted with chloroform, the extract was dried with anhydrous Na2SO4 and after removal of the chloroform, the residue was chromatographed over SiO2 employing CH2Cl2 --AcOEt (3:2) mixture as eluent. The eluate was evaporated to dryness in vacuo and the residue was recrystallized (EtOH-Hexane); yield 30 g (46%), mp 89°-90° C.
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([SH:13])[CH2:11][SH:12].[CH2:14]([O:16][C:17](=[O:26])[C@@H:18]([O:22][C:23](=[O:25])[CH3:24])[CH2:19][CH:20]=O)[CH3:15]>ClCCl>[CH2:14]([O:16][C:17](=[O:26])[C@@H:18]([O:22][C:23](=[O:25])[CH3:24])[CH2:19][CH:20]1[S:13][CH2:10][CH2:11][S:12]1)[CH3:15]
Reactant: SCCS
Reactant: CCOC(=O)[C@H](CC=O)OC(C)=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)[C@H](CC1SCCS1)OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 145 %

Procedure:
Boron trifluoride etherate (1.15 g, 81 mmol) was added to a stirred solution of 1,2-ethanedithiol (0.34 g, 3.65 mmol) and (S)-2-acetoxy-4-oxobutanoic acid ethyl ester (0.46 g, 2.4 mmol) in dichloromethane (20 ml) at 0°. The mixture was stirred at room temperature overnight and ice/water added. The organic layer was separated, dried (MgSO4) and the solvent evaporated to give the sub-title compound (0.92 g).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].Cl.[NH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([O:42][CH3:43])[CH:36]=1.C(N(CC)CC)C>>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([S:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([O:42][CH3:43])[CH:36]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:23][CH:24]=1
Reactant: O=C(CSc1ccc(Br)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: COc1cc(CN)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)CSc2ccc(Br)cc2)C3)ccc1O

Procedure:
The title compound was synthesized in the manner of Example 81 from 2,2,2-trichloro-1-[10-{[(4-bromophenyl)thio]acetyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone of Example 80 and 4-aminomethyl-2-methoxyphenol hydrochloride in the presence of with one equivalent of triethylamine, m.p. 168° C. MS [(+)ESI, m/z]: 592 [M+H]+ Anal. Calcd for C29H26BrN3O4S: C, 58.79; H, 4.42; N, 7.09. Found: C, 58.65; H, 4.46; N, 6.86.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[C:10](N1C=CN=C1)([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11].C(Cl)Cl>ClCCCl>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11])[CH2:2]2
Reactant: OC1CN2CCC1CC2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(OC1CN2CCC1CC2)n1ccnc1

Procedure:
According to Method C, 3-quinuclidol is first reacted with a carbonyldiimidazole (DCI) in an inert solvent (e.g. DCM, 1,2-DCE) at room temperature in order to obtain the corresponding imidazole-1-carboxylic acid 1-azabicyclo[2.2.2]oct-3-yl ester. Then, arylalkylamine (II) is metalated in an inert solvent (e.g. THF) using BuLi and the ester was added at a temperature ranging from 0° C. to room temperature.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25].C(Br)(Br)(Br)[Br:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O>[Br:27][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25]
Reactant: COc1ccc2nc(-c3cc(C)c(OCCO)c(C)c3)[nH]c(=O)c2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3cc(C)c(OCCBr)c(C)c3)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-6-methoxy-3H-quinazolin-4-one (1.50 g, 4.41 mmol) in N,N-dimethylformamide (15 mL), carbon tetrabromide (1.60 g, 4.85 mmol), and triphenylphosphine (1.30 g, 4.85 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo and the product was purified by the Simpliflash system, using 1-2% methanol in CH2Cl2 as eluent, to give 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-6-methoxy-3H-quinazolin-4-one as a white solid. Yield: 1.77 g (quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>C(O)(=O)C.O>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-n2cccc2)cc1

Procedure:
To a stirred solution of methyl 4-aminobenzoate (7.6 g) in acetic acid (25 ml) was added 2,5-dimethoxytetrahydrofuran (6.6 g) dropwise and the reaction mixture was heated under reflux for 1 hour and then diluted with water. The resulting precipitated crystals were purified by column chromatography on silica gel. Recrystallization from ethyl acetate-hexane afforded the title compound as colorless plates (7.5 g, 74%), m.p. 128°-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]([NH:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:13])=[CH:9][N:10]=1)[C:5]([OH:7])=O.[C:21]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[N:10]=[CH:9][C:8]2[N:11]([CH3:21])[C:12](=[O:13])[N:14]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:5](=[O:7])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CCNC(=O)Nc1cnc(Cl)cc1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)CCn1c(=O)c2cc(Cl)ncc2n(C)c1=O
Temperature: 40 °C
Yield: 4.8 %

Procedure:
To a solution of 2-chloro-5-(3-(3-methoxy-3-oxopropyl)ureido)isonicotinic acid (33.8 g, 112 mmol) in acetone (386 mL) was added K2CO3 (46.4 g, 336 mmol) followed by CH3I (95.4 g, 672 mmol). The reaction was heated in a sealed tube at 40° C. for 24 h, cooled to RT, concentrated then diluted with EA (200 mL) and water (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 2:1) to give methyl 3-(6-chloro-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propanoate (1.6 g, 11% yield) as a yellow solid. LCMS: MH+ 298 and TR=2.857 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15][NH2:16])=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=O)[CH3:27])[CH:21]=1>CO.C(O)(=O)C>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15]/[N:16]=[C:26](/[C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)\[CH3:27])=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: CC(=O)c1cccnc1
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cccnc1
Temperature: 120 °C
Yield: 27.6 %

Procedure:
3-(Morpholinosulfonyl)benzohydrazide (40 mg, 0.140 mmol) and 1-(pyridin-3-yl)ethanone (16.98 mg, 0.140 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound as a solid (15 mg). 1H NMR (400 MHz, CDCl3): δ 9.53 (bs, 1H), 8.87 (s, 1H), 8.59 (m, 1H), 8.39 (m, 1H), 8.17 (m, 1H), 7.98 (m, 1H), 7.89 (d, 1H, J=8.0 Hz), 7.67 (t, 1H, J=8.0 Hz), 7.32 (m, 1H), 3.70 (m, 4H), 3.00 (m, 4H), 2.39 (s, 3H). ESI-MS: 389.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.C[Al](C)C.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C@@:26]([OH:52])([CH2:46][N:47]1[CH:51]=[N:50][CH:49]=[N:48]1)[C@H:27]([S:29][C@@H:30]1[CH2:35][O:34][C@@H:33]([C:36]2[CH:45]=[CH:44][C:39]([C:40](OC)=[O:41])=[CH:38][CH:37]=2)[O:32][CH2:31]1)[CH3:28]>>[C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:1][C:40](=[O:41])[C:39]2[CH:44]=[CH:45][C:36]([C@H:33]3[O:32][CH2:31][C@H:30]([S:29][C@H:27]([CH3:28])[C@:26]([C:20]4[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=4[F:18])([OH:52])[CH2:46][N:47]4[CH:51]=[N:50][CH:49]=[N:48]4)[CH2:35][O:34]3)=[CH:37][CH:38]=2)=[CH:3][CH:4]=1)#[N:13]
Reactant: N#Cc1ccc(N)c2ccccc12
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(C#N)c4ccccc34)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available 4-amino-1-naphthalenecarbonitrile (200 mg, 1.2 mmol), trimethylaluminium (1.1 ml, 1.07M n-hexane solution, 1.2 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (150 mg, 0.30 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (73 mg, yield 38%) as a pale yellow oil which was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [O:1]1[C:5]2=[N:6][C:7]3[C:13](=O)[O:12][C:10](=[O:11])[C:8]=3[CH:9]=[C:4]2[CH:3]=[CH:2]1.[NH2:15][C:16]([CH3:23])([CH:20]([CH3:22])[CH3:21])[C:17]([NH2:19])=[O:18].CCOCC>C1COCC1>[CH:20]([C:16]1([CH3:23])[C:17](=[O:18])[NH:19][C:13]([C:7]2[N:6]=[C:5]3[O:1][CH:2]=[CH:3][C:4]3=[CH:9][C:8]=2[C:10]([OH:12])=[O:11])=[N:15]1)([CH3:22])[CH3:21]
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: O=C1OC(=O)c2nc3occc3cc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C1(C)N=C(c2nc3occc3cc2C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
Furo[2,3-b]pyridine-5,6-Dicarboxylic anhydride (2.50 g, 0.013 mol) is suspended in 40 mLs anhydrous THF and (+)-2-amino-2,3-dimethylbutyramide (1.72 g, 0.013 mol) is added. The mixture is stirred under N2 at room temperature for 16 hours. The solution is poured into 150 mLs anhydrous ether, and the resulting solid is collected in 88.6% crude yield. The unpurified adduct is converted to the indicated product in the manner described in Example 38 for the racemic mixture. The (+)-isomer is recrystallized from absolute ethanol, and is isolated in 27.0% yield from the adduct., mp 244°-245° C. [α]D25 =44.5°.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][N:26]=1>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:25]5[N:26]=[CH:27][C:28]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)=[CH:29][N:30]=5)[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: Clc1ncc(-c2ccccc2)cn1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: c1ccc(-c2cnc(NC3CCN(CC45CC(c6ccccc64)c4ccccc45)CC3)nc2)cc1

Procedure:
Using a procedure similar to that described in Example 86 except starting with 4-amino-1-(9,10-dihydro-9,10-methanoanthracene-9-ylmethyl)piperidine (prepared as described in Example 8b) and 2-chloro-5-phenylpyrimidine the hydrochloride salt of the title compound was obtained as a white solid (60%), mp 292°-294° C.; MS(CI): 459 (M+H); NMR (300MHz, DMSO-d6): 9.95(br s, 1H), 8.70-8.66(m, 2H), 7.66-7.62(m, 3H), 7.47-7.33(m, 7H), 7.04-6.96(m, 4H), 4.46(s, 1H), 4.35-4.33(m, 2H), 4.25-4.00(br m, 1H), 3.0-3.35(m, 4H), 2.74(s, 2H), 2.15-1.91(m, 4H).
Reaction SMILES: [CH2:1]([C:8]1[O:12][CH:11]=[N:10][C:9]=1[C:13](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1OC=NC=1CO)C1C=CC=CC=1.S(Cl)([Cl:32])=O>>[CH2:1]([C:8]1[O:12][CH:11]=[N:10][C:9]=1[CH2:13][Cl:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ncoc1Cc1ccccc1
Reactant: O=S(Cl)Cl
Agent: OCc1ncoc1Cc1ccccc1
Product: ClCc1ncoc1Cc1ccccc1

Procedure:
5-Benzyl-4-oxazolecarboxylic acid is converted to 5-benzyl-4-hydroxymethyloxazole by the procedure of Example 135. Treating this hydroxymethyl compound with thionyl chloride gives 5-benzyl-4-chloromethyloxazole.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4].[H-].[Na+].Cl[C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][N:12]=1>O1CCCC1>[NH2:1][CH:2]([CH2:5][CH2:6][CH3:7])[CH2:3][O:4][C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][N:12]=1
Reactant: Clc1noc2ccccc12
Reactant: CCCC(N)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(N)COc1noc2ccccc12
Yield: 88.1 %

Procedure:
A solution of 2.86 g of 2-amino-1-pentanol in 2 ml of tetrahydrofuran is added to a suspension of 2.24 g of 60% (w/w) sodium hydride in 20 ml of tetrahydrofuran at 20°-25° C. and they are refluxed for two hours. Subsequently, under reflux, a solution of 4.3 g of 3-chloro-1,2-benzoisoxazole in 30 ml of tetrahydrofuran is added and refluxed for a further one hour. After cooling, the solvent is removed by distillation under reduced pressure. Ethyl acetate and water are added to the residue obtained, and after shaking, the organic layer is separated. The separated organic layer is washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and thereafter purified by a silica gel column chromatography [eluant:chloroform:methanol=20:1], to obtain 5.38 g of oily 3-(2-aminopentyloxy)-1,2-benzoisoxazole.
Reaction SMILES: C12(CO)CC3CC(CC(C3)C1)C2.[CH:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH:14]1[OH:23])[CH2:20]2.ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:40][C:41]1[C:42](F)=[CH:43][C:44]([F:56])=[C:45]([CH:55]=1)[C:46]([NH:48][S:49](=[O:54])(=[O:53])[N:50]([CH3:52])[CH3:51])=[O:47]>>[CH:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH:14]1[O:23][C:42]1[C:41]([Cl:40])=[CH:55][C:45]([C:46]([NH:48][S:49](=[O:54])(=[O:53])[N:50]([CH3:52])[CH3:51])=[O:47])=[C:44]([F:56])[CH:43]=1)[CH2:20]2
Reactant: OC1C2CC3CC(C2)CC1C3
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OC2C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace adamantan-1-ylmethanol with adamantan-2-ol and 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide (as prepared in Example 31), the title compound was obtained as a colorless solid (0.21 g, 38%): 1H NMR (300 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.33 (d, J=12.5 Hz, 1H), 4.81 (s, 1H), 2.87 (s, 6H), 2.08-2.03 (m, 4H), 1.84-1.71 (m, 8H), 1.54-1.50 (m, 2H); MS (ES−) m/z 429.2, 431.2 (M−1).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=O)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C([O-])(=O)C.[NH4+:30].[OH-].[NH4+]>>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH2:30])=[O:23])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)OCC
Agent: CC(=O)[O-]
Agent: [OH-]
Product: CCCc1nc2cnc3ccccc3c2n1CCCCC(N)=O
Temperature: 130 °C
Yield: 56.7 %

Procedure:
Ethyl 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanoate (5.4 g, 15.9 mmol), prepared as described in Parts A through C of Example 34) and ammonium acetate (11.0 g, 143 mmol) were sealed in a high-pressure vessel and heated for two days at 130° C. and then allowed to cool to ambient temperature. Ammonium hydroxide was added to adjust the mixture to a neutral pH. The mixture was then extracted with dichloromethane, and the combined extracts were washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 2.8 g of 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanamide, which was combined with material from another run.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Br[CH2:10][CH2:11][CH2:12][CH2:13]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:7]([O:6][C:4]([C:3]1([C:1]#[N:2])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:8]
Reactant: CCOC(=O)CC#N
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C#N)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl cyanoacetate (2.50 g, 22 mmol) and 1,4-dibromobutane (5.00 g, 23.0 mmol) were dissolved in anhydrous DMF (20 ml) under nitrogen and cesium carbonate (21.0 g, 64 mmoles) added with water bath cooling. After stirring at room temperature for 18 h the reaction was diluted with water and extracted with ethyl acetate (2×80 ml), the organic layers were combined and washed with water (40 ml) and saturated aqueous sodium chloride solution (25 ml). The organics were dried over magnesium sulphate, filtered and evaporated under reduced pressure to give 1-cyano-cyclopentanecarboxylic acid ethyl ester as an almost colourless oil (3.64 g, 98%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:18]1([CH2:24][CH2:25][CH2:26][CH:27]([NH2:37])[CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:37][CH:27]([CH2:26][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.9 %

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (1 g; 4.36 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (1.33 g; 4.38 mmol), triethylamine (1.22 mL; 8.75 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.92 g; 4.8 mmol) are added sequentially. The mixture is stirred for 18 hours at ambient temperature then concentrated in vacuo at 40° C. The residue is diluted with ethyl acetate (150 mL) and washed successively with water (150 mL), 0.1 N HCl (100 mL), saturated aqueous sodium bicarbonate (50 mL), and saturated brine (50 mL). The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (5%→40% ethyl acetate in hexanes) affording the desired product (0.77 g) as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[CH:20]=O.N1CCCCC1>C(O)C>[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[CH:20]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2C1=Cc1cc2ccccc2[nH]1
Temperature: 95 °C

Procedure:
A mixture of 2-oxindole (133 mg), indole-2-carbaldehyde (174 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (10 mg) in ethanol was heated in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in vacuum oven for overnight to give 3-(1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one.