Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][C:7](=O)[C:8]([CH3:12])([CH3:11])[NH:9][CH2:10][C:4]=2[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:11][C:8]1([CH3:12])[CH2:7][NH:6][C:5]2[N:14]=[CH:15][CH:2]=[CH:3][C:4]=2[CH2:10][NH:9]1
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CNc2ncccc2CN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 134.8 %

Procedure:
A suspension of 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydropyrido[2,3-e][1,4]diazepin-2-one (0.50 g, 1.8 mmol) in THF (15 mL) was cooled in an ice bath and treated dropwise with LiAlH4 (4.1 mL of a 1.0 M solution in THF, 4.1 mmol). After stirring for 30 min, the ice bath was removed and the solution was allowed to warm to room temperature. After heating to reflux overnight, the mixture was cooled in an ice bath. The reaction was quenched sequentially with H2O (0.15 mL), 15% NaOH (0.15 mL) and H2O (0.45 mL). After 5 min, the ice bath was removed and the mixture was stirred at room temperature for 1.5 h. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give the title compound (0.43 g, quantitative) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.90 (dd, J=4.9, 1.5 Hz, 1H), 7.17 (d, J=7.2 Hz, 1H), 6.61 (dd, J=7.2, 4.9 Hz, 1H), 4.85 (br s, 1H), 3.91 (s, 2H), 3.22 (d, J=4.5 Hz, 2H), 2.39 (br s, 1H), 1.20 (s, 6H); MS (ESI) m/e 178 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@@H:16]([OH:17])[CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].N[C@H]1[C@H](O)CN(C(OCC2C=CC=CC=2)=O)C1>>[CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@H:16]([OH:17])[CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)n1
Agent: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Product: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O)n1

Procedure:
Following the procedure for the preparation of benzyl(3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate but substituting benzyl(trans)-3-amino-4-hydroxypyrrolidine-1-carboxylate and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.78, 7.39, 6.41, 6.22, 5.18, 4.51–3.95, 3.40, 2.65, 1.31–1.26; (MS/CI) calcd for C20H26N4O3+H 371.4, found 370.9.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.C(N(CC)C(C)C)(C)C.C(N=C=NCCCN(C)C)C.[Br:31][C:32]1[S:36][C:35]2=[N:37][C:38]([C:40]([OH:42])=O)=[CH:39][N:34]2[CH:33]=1.[C:43]([C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH2:54])=[CH:49][CH:48]=1)([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl.CN(C)C=O>[Br:31][C:32]1[S:36][C:35]2=[N:37][C:38]([C:40]([NH:54][CH2:53][C:50]3[CH:51]=[CH:52][C:47]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:48][CH:49]=3)=[O:42])=[CH:39][N:34]2[CH:33]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: CC(C)(C)c1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CNC(=O)c2cn3cc(Br)sc3n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydroxybenzotriazole (109 mg, 0.81 mmol), N,N-diisopropylethylamine (0.23 ml, 1.34 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (155 mg, 0.81 mmol) were sequentially added to a the solution of 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid (supplied by Chemizon, 200 mg, 0.81 mmol) in a solvent mixture of methylene chloride (5 ml) and N,N-dimethyl formamide (2 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the addition of (4-(tert-butyl)phenyl)methanamine (0.42 ml, 2.78 mmol) at room temperature, the reaction mixture was stirred at room temperature for 24 hours, then diluted with methylene chloride. The reaction mixture was partitioned between methylene chloride and water. The aqueous layer was extracted with methylene chloride. The combined organic layer was washed with brine, then dried over anhydrous magnesium sulfate. After concentration, water was added to the residue. Filtration, followed by drying in vacuo, gave the title compound, 2-bromo-N-(4-(tert-butyl)benzyl)imidazo[2,1-b]thiazole-6-carboxamide, as a solid (148 mg, 87% yield).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:46]=[CH:45][C:25]([O:26][C:27]2[CH:44]=[CH:43][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:37][CH2:38][C:39]([O:41]C)=[O:40])=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:8]([CH2:21][C:22]1[CH:46]=[CH:45][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:37][CH2:38][C:39]([OH:41])=[O:40])=[O:36])=[CH:43][CH:44]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CNC(=O)CCCOc1ccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)NCC(=O)O)cc2)cc1

Procedure:
The product from Example 251A was treated with 22N aqueous sodium hydroxide: 1 tetrahydrofuran: 1 ethanol (2 ml) at room temperature overnight. The reaction mixture acidified with 1N hydrochloric acid to pH 3-4, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue purified by HPLC to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.13-12.81 (br.s, 1 H), 8.94 (s, 1 H), 8.18 (t, 1 H), 7.14-7.34 (m, 7 H), 6.98 (m, 7 H), 6.82 (d, 2 H), 4.05 (s, 2 H), 4.00 (s, 2 H), 3.95 (t, 2 H), 3.74 (d, 2 H), 2.91 (s, 3 H), 2.38 (s, 3 H), 2.30 (t, 2 H), 1.93 (m, 2 H); MS (ESI+) m/z 632 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[N:5][N:6]=1.[C:16](OCC)(=[O:21])[CH2:17][C:18]([CH3:20])=O>O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][S:7][C:4]2[S:3][C:2]3=[N:1][C:18]([CH3:20])=[CH:17][C:16](=[O:21])[N:6]3[N:5]=2)=[CH:10][CH:11]=1
Reactant: Nc1nnc(SCc2ccc(Cl)cc2)s1
Reactant: CCOC(=O)CC(C)=O
Solvent: O
Product: Cc1cc(=O)n2nc(SCc3ccc(Cl)cc3)sc2n1
Reaction time: 0.75 h
Yield: 84 %

Procedure:
Twenty point two (20.2) g of the thus obtained 2-amino-5-(4-chlorobenzylthio)-1,3,4-thiadiazole and 12.2 g of ethyl acetoacetate were mixed with 24 g of polyphosphoric acid and the mixture was stirred at 130°~150° C. for 45 minutes. After cooling, water was added to the mixture, the mixture was extracted with chloroform, and the organic layer was washed with a sodium hydrogen carbonate aqueous solution and water respectively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was recrystallized from ethanol and thus 21.3 g of 2-(4-chlorobenzylthio)-7-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.CO>O1CCCC1>[N:1]1([C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(C(=O)N2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C(=O)N2CCCC2)cc1

Procedure:
29.0 g (0.146 mol) of monomethyl terephthalate chloride was reacted with 14.2 g (200 mmol) of pyrrolidine and 21.0 g (208 mmol) of triethylamine in 350 ml of dichloromethane. After the treatment in an ordinary manner, methyl 4-(1-pyrrolidylcarbonyl)benzoate was obtained. 29.0 g of the ester was hydrolyzed with 12.0 g of sodium hydroxide in a mixed solvent comprising 70 ml of water, 70 ml of methanol and 70 ml of tetrahydrofuran. After the completion of the reaction, the solvent was evaporated. 1 N hydrochloric acid was added to the residue and the obtained mixture was treated with dichloromethane as the extraction solvent in an ordinary manner to obtain the title compound.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=O.Cl.[CH2:28](O)C>>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23][CH2:24][CH3:28])=[O:22])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(-c2ccc(CCCNC(=O)C(F)(F)F)cc2)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(-c2ccc(CCCN)cc2)cc1

Procedure:
A mixture of methyl 4′-[3-[(trifluoroacetyl)amino]-propyl]-1,1′-biphenyl-4-carboxylate (920 mg), 4N hydrochloride in ethanol (2 ml) and ethanol (2 ml) was refluxed for 18 hours. The mixture was evaporated in vacuo. The residue was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (chloroform:methanol=100:1) to give ethyl 4′-(3-aminopropyl)-1,1′-biphenyl-4-carboxylate (200 mg) as a colorless foam.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([N+:15]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:4]([NH2:15])[CH:3]=1
Reactant: Cc1ccc(Oc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: Cc1ccc(Oc2ccccc2)c(N)c1
Yield: 92.3 %

Procedure:
The product from Example 41a (884 mg, 3.86 mmol) was treated with SnCl2 (3.5 g, 19.0 mmol) for 24 h following the procedure from Example 1f giving the title compound as a yellow oil (710 mg, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]=[C:9]2[OH:12])=[CH:4][CH:3]=1.[C:13]([O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:13]([O:17][C:18](=[O:27])[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][N:8]2[N:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=3)[C:9]2=[O:12])=[CH:23][CH:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: Oc1nncc2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Cn2ncc3ccc(Br)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 7-bromo-1-hydroxy-3-azaisoquinoline (7.02 g, 28.2 mmol) in dimethylformamide (75 mL) is treated with 4-bromomethylbenzoic acid tert-butyl ester (12.5 g, 36.7 mmol) and cesium carbonate (11.94 g, 36.7 mmol), then stirred overnight at room temperature. The dimethylformamide is evaporated in vacuo, the residue is diluted with ethyl acetate, washed with 1N HCl, the organic portion washed with brine, dried over MgSO4 and evaporated to dryness. The residue is triturated with hot hexanes/ethyl acetate, cooled to room temperature, and the solid is collected by filtration and dried to give the desired product. Step (2): 4-[1-oxo-7-(3-phenyl-prop-1-ynyl)-1H-3-azaisoquinolin-2-ylmethyl]benzoic acid tert-butyl ester
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:19]2[O:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:22]#[N:23])[CH:16]=3)[C:11](=[O:24])[C:10]=2[CH:9]=1)(=[O:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:19]2[O:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:22]4[NH:27][N:26]=[N:25][N:23]=4)[CH:16]=3)[C:11](=[O:24])[C:10]=2[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOc1ccc2oc3cc(C#N)ccc3c(=O)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1ccc2oc3cc(-c4nnn[nH]4)ccc3c(=O)c2c1

Procedure:
The cyanoxanthone from step (B) (2.9 g), sodium azide (0.61 g), ammonium chloride (0.53 g) and dimethylformamide (50 ml) were heated together at 125° for 8 h. The reaction mixture was poured into an iced aqueous solution of hydrochloric acid (excess) and the product filtered off and dried. Recrystallisation from dimethylformamide yielded the title compound, m.p. 216°-218° C.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:29])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]3[O:23][CH2:22][C@H:21]([O:24][CH2:25][C:26]([NH2:28])=[O:27])[CH2:20][C:18]3=2)[CH:13]=[N:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C1COCC1>[OH:8][C@H:9]([CH3:29])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]3[O:23][CH2:22][C@H:21]([O:24][CH2:25][C:26]([NH2:28])=[O:27])[CH2:20][C:18]3=2)[CH:13]=[N:12]1
Reactant: C[C@H](Cn1ncc2ccc3c(c21)C[C@@H](OCC(N)=O)CO3)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Product: C[C@@H](O)Cn1ncc2ccc3c(c21)C[C@@H](OCC(N)=O)CO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
The product from Step B (0.44 g, 1.05 mol) was dissolved in THF (20 mL) and a solution of tetrabutylammonium fluoride in THF (1 M, 2.1 mL, 2.1 mmol) was added; this mixture was stirred for 2 h at room temperature. A saturated aqueous solution of sodium bicarbonate (100 mL) was added and the mixture was saturated with sodium chloride and extracted with ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4) and evaporated to give a yellow oil (0.47 g) which was purified by chromatography (silica gel, gradient, ethyl acetate; 5% methanol in ethyl acetate; 10% methanol in ethyl acetate) to give a colorless oil (0.30 g, 94%): LC/MS (+APCI) m/z 306.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:6][CH2:5]1)[CH3:3].Br[C:18]1[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][CH:23]=1>>[CH3:3][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][CH:23]=3)[CH2:15][CH2:16]2)[CH2:6][CH2:5]1)[CH3:1]
Reactant: CC(C)N1CCC(CC2CCNCC2)CC1
Reactant: FC(F)(F)c1ncc(Br)cn1
Product: CC(C)N1CCC(CC2CCN(c3cnc(C(F)(F)F)nc3)CC2)CC1

Procedure:
Example 36 was prepared using an analogous process to that described in Example 35 from 1-(1-methylethyl)-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 4) and 5-bromo-2-trifluoromethylpyrimidine (may be prepared as described in F. Cottet and M. Schlosser, Eur. J. Org. Chem., 2002, 327). 1H-NMR and mass spectral data were consistent with structure. MS electrospray (+ion) 371 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:4][CH2:3]1.O[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[CH2:4][CH2:3]1
Reactant: N#Cc1cccc(O)c1
Reactant: CN1CCC(CCCCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(CCCCOc2cccc(C#N)c2)CC1
Yield: 70.6 %

Procedure:
To a 0° C. solution of 4-(1-methyl-piperidin-4-yl)-butan-1-ol (0.74 g, 4.37 mmol), 3-hydroxy-benzonitrile (0.52 g, 4.37 mmol), and 3 mmol/g polymer supported PPh3 (2.30 g, 8.73 mmol) in THF (40 mL) was added diisopropyl azodicarboxylate (1.72 mL, 8.73 mmol) dropwise. After 6 h the mixture was filtered and concentrated. Purification by Method 1 afforded 840 mg (71%) of a yellow oil. MS (ESI): mass calcd for C17H24N2O, 272.19; m/z found, 273.4 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.38-7.33 (m, 1H), 7.24-7.20 (m, 1H), 7.14-7.09 (m, 2H), 3.96 (t, J=6.4, 2H), 2.88-2.80 (m, 2H), 2.26 (s, 3H), 1.94-1.84 (m, 2H), 1.82-1.73 (m, 2H), 1.72-1.64 (m, 2H), 1.52-1.42 (m, 2H), 1.34-1.17 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH2:36])[CH:34]=[CH2:35]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:36][CH2:33][CH:34]=[CH2:35])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C=CCN
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C=CCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 130 ml tetrahydrofuran was stirred at room temperature for 3 hours. Under a nitrogen atmosphere, N-allylamine (1.60 g, 0.028 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to a solid, which was placed under high vacuum over the weekend. The solid residue was dissolved in isopropyl alcohol, filtered, and diluted with water to initiate crystallization, then refrigerated overnight. The solid was collected by filtration, washed with water, and dried under high vacuum at 50° C. overnight to give 3.0 g (66%) of title compound, mp 208°-9° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[C:16](O)(=O)CC(O)=O.N1C=CC=CC=1.Cl>O>[C:11]([C:6]1[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=1[C:8]([OH:10])=[O:9])(=[O:12])[CH3:16]
Reactant: O=C(O)CC(=O)O
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Reaction time: 1.5 h
Yield: 41.7 %

Procedure:
A mixture comprising 57.2 g of tetrachlorophthalic anhydride, 25.0 g of malonic acid and 60 ml of pyridine was stirred at 70° to 75° C. for 1.5 hours. After adding 200 ml of water and 200 ml of conc. hydrochloric acid, the mixture was boiled for 10 minutes. After allowing to cool, the precipitate was collected by filtration and dried. The solid product thus obtained was extracted with 600 ml of hot ether. The extract was concentrated and the residue was recrystallized from dilute ethanol. Thus, 25.2 g of 2-acetyl-3,4,5,6-tetrachlorobenzoic acid was obtained. NMR (270 MHz, CDCl3): δ 2.03 (s,3H). IR (KBr) ν (C=O) 1770 cm-1, ν (OH) 3380 cm-1.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:21][C:11]2=[CH:12][N:13]=[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:15]=[C:10]2[CH:9]=1)=[O:7])[CH3:4].Br[CH2:23][C:24]1[CH:28]=[C:27]([C:29]2[S:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[O:26][N:25]=1>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:21]([CH2:23][C:24]2[CH:28]=[C:27]([C:29]3[S:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[O:26][N:25]=2)[C:11]2=[CH:12][N:13]=[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:15]=[C:10]2[CH:9]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc2cc(OCCOC)ncc2[nH]1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCCOC)ncc2n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
105 mg (4.16 mmol) NaH (96%) were added to a solution of 5-(2-Methoxy-ethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester in 50 mL absolute DMF and the mixture was stirred for 30 min. at room temperature. 1.05 g (3.78 mmol) 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole were added and the the mixture and stirring was continued for 3 h. After addition of 21 mg (0.832 mmol) NaH (96%) and 210 mg (0.756 mmol) 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole and standing overnight the mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 and the solution washed with saturated NaHCO3 solution. The solvent was removed in vacuo and the residue purified by flash chromatography over silica gel using n-heptane/ethyl acetate=3/2 as solvent. The fractions containing the product were concentrated.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.O>C1COCC1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In THF (250 ml) was dissolved 4-nitrobenzylbromide (25.0 g), and to the mixture was added morpholine (25.2 ml) at 0° C. The reaction mixture was stirred for 15 hours at room temperature. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give 4-(4-nitrobenzyl)morpholine (25.5 g) as pale yellow crystals. A portion of the crystals was recrystallized from diisopropylether to give pale yellow crystals which were used for various analyses. mp 79-80° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH:14]([CH:17]=[O:18])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[K+].[BH4-].[Na+]>>[OH:18][CH2:17][C@H:14]1[CH2:13][CH2:12][C@H:11]([CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH2:16][CH2:15]1
Reactant: N#Cc1ccc(CCC2CCC(C=O)CC2)cc1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Product: N#Cc1ccc(CC[C@H]2CC[C@H](CO)CC2)cc1
Temperature: 0 °C
Yield: 73.4 %

Procedure:
A mixture of 21.9 g of 4-[2-(p-cyanophenyl)ethyl]cyclohexanecarboxaldehyde (trans/cis=4:1) and 167 ml of 0.1N methanolic potassium hydroxide solution was cooled to 0° C. while stirring and gassing with nitrogen, treated portionwise within 20 minutes with 3.5 g of sodium borohydride and thereafter stirred for a further 30 minutes at 0° C. Subsequently, the grey suspension was poured cautiously on to 420 ml of ice-water and extracted three times with 300 ml of methylene chloride each time. The organic phases were washed twice with 150 ml of water each time, dried over sodium sulphate and concentrated in vacuo at 50° C. The colourless, crystalline residue of p-[2-(4-hydroxymethylcyclohexyl)ethyl]benzonitrile (22.0 g, trans/cis=89.4:10.6) was dissolved in 100 ml of ethyl acetate while warming, treated with 100 ml of hexane and cooled to 15° C. while stirring, whereby crystallization occurred. The mixture was then treated with a further 300 ml of hexane while stirring, suction filtered (rinsing with hexane) and the precipitate was dried in vacuo at 50° C. The mother liquor was worked-up in an analogous manner and then the two crystallizates (a total of 17.3 g) were recrystallized from ethyl acetate/hexane. There were obtained 16.2 g (74%) of pure p-[2-(trans-4-hydroxymethylcyclohexyl)ethyl]benzonitrile as colourless crystals with m.p. 119.2°-121.1° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13]Br)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:15]#[N:16].[K+].O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][C:15]#[N:16])[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1cc(CBr)cn1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)n1cc(CC#N)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 4-bromomethyl-pyrazole-1-carboxylic acid tert-butyl ester (1.0 g, 3.5 mmol) in DMSO (25 mL) was added potassium cyanide (0.228 g, 3.5 mmol), and the reaction was stirred for 15 minutes at room temperature. The mixture was poured into H2O and extracted with EtOAc. The combined organic layers were dried and concentrated to give the title compound, along with some starting material and the unbrominated starting material from the previous step. The material was dissolved in DMSO (10 mL), and potassium cyanide (0.100 g, 1.5 mmol) was added. The reaction was stirred for 1 hour at room temperature, and then worked-up, dried, and concentrated to give the title compound, contaminated with a small amount of 4-methyl-pyrazole-1-carboxylic acid tert-butyl ester.