Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH3:9][N:10]1[CH:14]2[CH2:15][CH:16](O)[CH2:17][CH:11]1[CH2:12][CH2:13]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C>[CH3:9][N:10]1[CH:14]2[CH2:13][CH2:12][CH:11]1[CH2:17][CH:16]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[CH2:15]2
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CN1C2CCC1CC(O)C2
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN1C2CCC1CC(n1cc([N+](=O)[O-])cn1)C2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 4-Nitro-1H-pyrazole (10 g, 88.4 mmol) in DGM:DMF (3:1, 400 mL) were added Tropine (12.5 g, 88.4 mmol, 1 eq.), triphenyl phosphine (69.5 g, 265 mmol), followed by di-tert-butyl azodicarboxylate (61 g, 265 mmol) portionwise at 10-15° C. The reaction mixture was stirred at RT for 4 days. It was then concentrated under reduced pressure. The crude was purified by flash chromatography on silica (PetEther/EtOAc) to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.31 (s, 1H), 4.92-4.86 (m, 1H), 3.99 (m, 2H), 2.66-2.56 (m, 5H), 2.26-2.17 (m, 4H), 2.06-2.01 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Br:47][C:48]1[C:53]([CH3:54])=[CH:52][C:51](O)=[CH:50][C:49]=1[CH3:56]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:14][C:51]2[CH:52]=[C:53]([CH3:54])[C:48]([Br:47])=[C:49]([CH3:56])[CH:50]=2)[CH:11]([CH3:12])[CH3:13])=[CH:6][CH:5]=1
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: COC(=O)c1ccc(C(O)C(C)C)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(Oc2cc(C)c(Br)c(C)c2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-2-methyl-propyl)-benzoic acid methyl ester (5000 mg, 24.04 mmol) in toluene (240 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 9098 mg, 36.06 mmol) at 0° C., followed by the additions of tributylphosphine (8.98 mL, 36.06 mmol) and 4-bromo-3,5-dimethyl-phenol (5798 mg, 28.85 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving the titled compound (5540 mg).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([OH:16])[C:14]=1[I:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8].CN(C=O)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([OH:16])[C:14]=1[I:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cc(O)c(I)c(O)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(O)c(I)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% oil, 1.33 g) was added to a mixture of ethyl 3,5-dihydroxy-4-iodobenzoate (5.00 g) and DMF (50 mL), and the resultant mixture was stirred at 0° C. for 30 minutes in a nitrogen atmosphere. Benzyl bromide (2.78 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.94 g).
Reaction SMILES: [I-].[K+].CS(O[CH2:8][CH2:9][O:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[C:23]([F:35])[CH:22]=2)[NH:13][N:12]=1)(=O)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][C@@H:37]1[CH2:41][OH:42]>>[F:35][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([O:10][CH2:9][CH2:8][N:36]4[CH2:40][CH2:39][CH2:38][C@@H:37]4[CH2:41][OH:42])[C:19]=23)[CH:26]=[CH:25][C:24]=1[O:27][C:28]1[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1
Reactant: OC[C@H]1CCCN1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCOS(C)(=O)=O)c34)cc2F)cn1
Agent: [I-]
Agent: [K+]
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCC[C@@H]5CO)c34)cc2F)cn1
Yield: 30 %

Procedure:
The procedure described in Example 23 was repeated (except that potassium iodide was not used) using 2-{[4-({3-fluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate (prepared as described in Example 20) and (R)-2-pyrrolidinemethanol to give the title compound in 30% yield; NMR Spectrum: 1.51 (m, 1H), 1.65 (m, 2H), 1.80 (m, 1H), 2.33 (q, 1H), 2.45 (s, 3H), 2.57 (m, 1H), 2.78 (dt, 1H), 3.14 (t, 1H), 3.28 (hidden by DMSO, 2H), 4.41 (t, 2H), 4.47 (br s, 1H), 7.25 (m, 3H), 7.56 (d, 1H), 7.85 (td, 1H), 8.01 (dd, 1H), 8.24 (d, 1H), 8.37 (s, 1H), 8.59 (br s, 1H); Mass Spectrum: 480 (MH+).
Reaction SMILES: [CH2:1]([CH:6]([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH:21]=O)[CH2:17][CH2:16]1)=[O:14]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[O:10][CH2:9][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][O:8]2)[CH2:17][CH2:16]1)=[O:14]
Reactant: COC(=O)C1CCC(C=O)CC1
Reactant: CCCCCC(CO)CO
Solvent: Cc1ccccc1
Product: CCCCCC1COC(C2CCC(C(=O)OC)CC2)OC1
Yield: 85.1 %

Procedure:
2-Pentyl-1,3-propanediol 17.0 g (116 mol) and 4-formylcyclohexane carboxylic acid methyl ester 18.8 g (111 mmol) were dissolved in toluene 120 ml, and PTS 1.0 g was added, and the mixture was refluxed with heating for 3 hours while removing water formed with Dien-Stark. The reactant was washed with a saturated sodium bicarbonate aqueous solution, and then with saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=4/1) to obtain 4-(5-pentyl-1,3-dioxane-2-yl)cyclohexanecarboxylic acid methylester 28.2 g (94.5 mmol). The yield was 85.1% from 4-formylcyclohexanecarboxylic acid methylester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](Cl)(Cl)=[S:10].C(N(CC)CC)C>C1COCC1>[SH:10][C:9]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2
Reactant: S=C(Cl)Cl
Reactant: Nc1cccnc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Sc1nc2ncccc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 9.8 %

Procedure:
To a solution of 2,3-diaminopyridine (286 mg, 2.62 mmol) in THF (10 ml) were added thiophosgene (300 mg, 2.62 mmol) and triethylamine (265 mg, 2.62 mmol), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:sat. ammonia methanol=10:1) to provide 39 mg (yield 10%) of 2-mercaptoimidazolo[4,5-b]pyridine.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1.[CH3:15]OS(OC)(=O)=O.[OH-].[Na+]>CN(C)C=O>[CH3:15][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)O)c2ccccc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
A cooled (0° C.) suspension of 60% sodium hydride-oil dispersion (0.96 g, 24 mmol) in anhydrous N,N-dimethylformamide (15 mL) under nitrogen was treated in portions with indole-3-carboxylic acid (1.62 g, 10 mmol), and the mixture was stirred at 45°±5° C. for 30 minutes. Dimethylsulfate (3.03 g, 24 mmol) was added, and the mixture was heated to 100° C. for 30 minutes, cooled, and added to ice water (100 mL). The suspension was filtered and the wet solid was washed with water and taken up in 50% aqueous methanol (40 mL). The mixture was treated with 50% aqueous sodium hydroxide (3.0 g, 37.5 mmol) and refluxed for 30 minutes, then the methanol was removed in vacuo and replaced with water. The aqueous solution was extracted with ether (50 mL), then acidified with 3N HCl to pH 3 (15 mL). The suspension was filtered and the solid was washed with water and dried exhaustively m vacuo in the presence of Drierite. Recrystallization from acetonitrile afforded 1.32 g (75%) of colorless crystals; mp 201°-202° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[BrH:11].Br.[NH+]1C=CC=CC=1.O>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH2:9][Br:11]
Reactant: Br
Reactant: CC(=O)c1ccccc1C
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.0 g of 2'-methylacetophenone in 60 ml of acetic acid was added successively 9.7 ml of 47% hydrobromic acid and 8.6 g of pyridinium hydrobromide perbromide, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and a saturated sodium carbonate solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure to give 5.4 g of the title compound as a colorless oily material.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[S:9])[O:8][C:4]=2[CH:3]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][CH3:14])[O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2[nH]c(=S)oc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nc2ccc(C)cc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Methyl-1,3-benzoxazole-2(3H)-thione (375 mg, 2.27 mmol) was dissolved in THF (2.0 mL), and iodomethane (1610.8 mg, 11.35 mmol) and potassium carbonate (627.36 mg, 4.54 mmol) were added. This reaction mixture was stirred vigorously at rt overnight. The reaction mixture was filtered and the solid was rinsed with additional THF. The filtrate was concentrated in vacuo to a yellow solid. The solid was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried with MgSO4, and concentrated. The solid was dried for 1 h in a 50° C. oven. The product 6-methyl-2-(methylsulfanyl)-1,3-benzoxazole was obtained as yellow-solid (145 mg, 35.6%). 1H NMR (300 MHz, DMSO-d6) δ 7.50 (d, 1H), 7.20 (s, 1H), 7.10 (d, 1H), 2.78 (s, 3H), 2.42 (s, 3H); LC-MS ret. time 2.90 min (method 2), m/z 180.1 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]=[O:17]>O1CCCC1>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:16]([NH:15][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:17])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)CN=C=O
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)NC1CCN(Cc2ccccc2)CC1
Yield: 93.8 %

Procedure:
2 g of 4-amino-1-benzylpiperidine was dissolved in 15 ml of tetrahydrofuran. After adding 1.6 g of ethyl isocyanatoacetate, the resulting mixture was heated under reflux for 1 hour. Then the reaction mixture was concentrated under reduced pressure to thereby give 3.15 g of the title compound as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1.CO>O1CCCC1.[C].[Pd]>[NH2:30][C:28]1[CH:27]=[CH:26][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:29]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCC(CN2CCCC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCCC4)CC3)c2)c(F)c1
Reaction time: 10 h
Yield: 99.9 %

Procedure:
4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]amide (290 mg) was dissolved in tetrahydrofuran (7 ml) and methanol (7 ml) under a nitrogen atmosphere, and then 10% palladium carbon (139 mg) was added, followed by stirring under a hydrogen atmosphere for 10 hrs. The reaction mixture was filtered to remove the catalyst, and the catalyst was washed with methanol. The filtrate was concentrated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing a target compound were concentrated to provide a crude product of 4-(pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (270 mg) as white foam.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:8].[NH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:22][CH3:23])[C:16]=2[O:20][CH3:21])[C:11]1=[O:24].C([BH3-])#N.[Li+].O1CCOCC1.Cl>CO>[ClH:8].[CH:1]1([NH:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:22][CH3:23])[C:16]=3[O:20][CH3:21])[C:11]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: COc1ccc2c(c1OC)CCC(N)C2=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Li+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2c(c1OC)CCC(NC1CCCCC1)C2=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a mixture of 200 volume parts of dry methanol and 200 volume parts of cyclohexanone is dissolved 10 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride and under nitrogen sparging and cooling at 0° C, there is added 9 parts of a molecular compound consisting of 1 mole lithium cyanoborohydride and 2 moles dioxane (LiBH3CN.2C4H8O2). At a constant temperature of 5° C, the reaction mixture is stirred for 2 hours. After the addition of dilute hydrochloric acid, the methanol is distilled off. The remaining mixture is washed with benzene and evaporated to dryness under reduced pressure. The residue is dissolved in ethanol, treated with activated carbon and recrystallized from a mixture of ethanol and ethyl ether. The procedure yields 9.65 parts of 2-cyclohexylamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride as colorless crystals melting at 180°-190° C (decomposition).
Reaction SMILES: Cl[C:2]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH2:13][CH2:12][CH:11]([S:14]([CH2:17][CH:18]2[CH2:20][CH2:19]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:5].[CH3:33][O-:34].[Na+].O>CO>[CH:18]1([CH2:17][S:14]([CH:11]2[CH2:12][CH2:13][C:8]([CH2:7][NH:6][C:4](=[O:5])[C:3]3[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:2]=3[O:34][CH3:33])([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH2:9][CH2:10]2)(=[O:16])=[O:15])[CH2:20][CH2:19]1
Reactant: C[O-]
Reactant: O=C(NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1)c1ccc(C(F)(F)F)nc1Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(C(F)(F)F)ccc1C(=O)NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A solution of 2-chloro-N-(4-cyclopropylmethanesulfonyl-1-cyclopropylmethylcyclohexylmethyl)-6-trifluoromethylnicotinamide (50 mg, 0.10 mmol) in methanol (5 ml) was treated with sodium methoxide (11 mg, 0.20 mmol) and the mixture was allowed to stir at ambient temperature for 1 hour then heated under reflux for 4 hours. Water (1 ml) was added and the solvent evaporated. The residue was partitioned between dichloromethane (5 ml) and water (5 ml) and the layers separated using a 5 micron PTFE frit and the filtrate was evaporated. The residue was purified by preparative plate chromatography on silica eluting with 10% ethyl acetate in dichloromethane. Collecting the appropriate band followed by trituration of the silica with ethyl acetate, filtration and evaporation gave a colourless oil (47 mg, 95%). 1H NMR δ (ppm)(CDCl3): 8.67 (1H, d, J=7.6 Hz), 7.92 (1H, s), 7.44 (1H, d, J=7.6 Hz), 4.15 (3H, s), 3.65 (2H, d, J=6.1 Hz), 2.94-2.89 (3H, m), 2.07-1.84 (6H, m), 1.40-1.32 (2H, m), 1.25-1.15 (3H, m), 0.78-0.70 (3H, m), 0.57-0.53 (2H, m), 0.42 (2H, q, J=5.3 Hz), 0.07 (2H, q, J=5.0 Hz). MS (m/e)=489.
Reaction SMILES: [C:1]([CH:3]1[C:12](=[O:13])[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]2[C:14]([CH2:17][CH2:18][CH3:19])=[N:15][N:16]=[C:4]12)#[N:2].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([N:16]1[C:4]2=[C:3]([C:1]#[N:2])[C:12](=[O:13])[N:11]3[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]3)=[C:5]2[C:14]([CH2:17][CH2:18][CH3:19])=[N:15]1)(=[O:22])[CH3:21]
Reactant: CCCC1=NN=C2C1=C1C=CC=CN1C(=O)C2C#N
Reactant: CC(=O)OC(C)=O
Product: CCCc1nn(C(C)=O)c2c(C#N)c(=O)n3ccccc3c12

Procedure:
A mixture of 80 g of 4-cyano-1-propyl-5H-pyrazolo-[4,3-a]quinolizin-5-one (S-1) and 2.0 l of acetic anhydride was heated under reflux for 18 hours. The solvent was evapolated under reduced pressure and the residual crystals were washed with water (0.5 l), methyl alcohol (0.5 l) and chloroform (0.5 l) successively to give 84 g of 3-acetyl-4-cyano-1-propyl-5H-pyrazolo-[4,3-a]quinolizin-5-one as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]#[N:19].[CH3:20]B(O)O.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[CH3:20][C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: CB(O)O
Reactant: N#Cc1ccc(-c2ncccc2C(F)(F)F)nc1Cl
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(-c2ncccc2C(F)(F)F)ccc1C#N
Temperature: 115 °C
Reaction time: 0.5 h

Procedure:
In a sealed tube, dissolve 6-chloro-3′-trifluoromethyl-[2,2′]bipyridinyl-5-carbonitrile (242 mg, 0.853 mmol), CH3B(OH)2 (300 mg, 5.10 mmol), K2CO3 (1.6 g, 12 mmol), and Pd(PPh3)4 in a solution of dioxane (10 mL) and H2O (2 mL). Bubble argon through the mixture for 30 minutes and seal. Heat the mixture at 115° C. overnight. Cool the mixture to room temperature. Add H2O (20 mL) and extract with EtOAc (3×20 mL). Combine the organic extracts and wash with brine (60 mL). Dry the organic layer over Na2SO4 and remove the solvent under reduced pressure. Purify the crude product using silica gel chromatography eluting with EtOAc/hexane (1:1) to yield the title compound. MS 264.07 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[OH:15].[CH3:16]O>>[CH3:16][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([I:5])=[C:7]([OH:15])[CH:8]=1
Reactant: CO
Reactant: O=C(O)c1ccc(I)c(O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(I)c(O)c1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
5 ml of thionyl chloride was added to 120 ml of MeOH at 0° C. The solution was stirred for 10 min and 20 g of 4-Iodo-3-hydroxy-benzoic acid was added. The reaction was stirred for 16 h at RT then heated to 50° C. for 3 h. The solvents were removed under reduced pressure. The residue was used directly in the next step. Yield 21 g
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[CH:11]=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[C:13]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:14][C:9]2=[N:8][CH:7]=1)=[O:5])C.O[Li].O.Cl>CO.O>[C:20]([O:19][C:17]([NH:16][CH2:15][C:13]1[C:12]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[CH:11][N:10]2[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=[C:9]2[CH:14]=1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1cnc2cc(CNC(=O)OC(C)(C)C)c(-c3ccc(Cl)cc3Cl)cn12
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cc2ncc(C(=O)O)n2cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.3 %

Procedure:
To a suspension of 7-(tert-butoxycarbonylamino-methyl)-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (1.39 g, 2.99 mmol) in MeOH (24 mL) and water (12 mL) was added LiOH.H2O (377 mg, 8.98 mmol) in one portion. The slurry was stirred at RT for 14 h then the clear solution was acidified to pH 5 by the addition of 2.0 M HCl in water. The resulting precipitate was filtered, the solid washed with water and dried under vacuum to yield the title compound (1.25 g, 2.76 mmol, 92%) as a colorless solid, which was used in the next step without further purification. MS: 436 [M+1]+; HPLC: AtRet=1.76.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N+:22]([O-])=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1.CNC.[H][H]>C1(C)C=CC=CC=1.[C].[Pt]>[OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N:22]=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1
Reactant: [H][H]
Reactant: CCC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)CC)c1
Agent: [Pt]
Agent: CNC
Solvent: Cc1ccccc1
Product: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1
Yield: 96 %

Procedure:
36.7 g (0.1 mol) of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole-N-oxide, 0.1 g of platinum carbon, 150 ml of a toluene solvent and 7 g of 50% dimethylamine were charged into a 500-ml four neck flask. After the air in the flask had been replaced by nitrogen, the resultant mixture was agitated at room temperature. Hydrogen was then supplemented for the amount of hydrogen absorbed by the mixture, which was then subjected to reaction until no more hydrogen was absorbed by it. After the reaction had been completed, the catalyst was filtered off, and part of the filtrate was subjected to quantitative analysis using gas chromatography (GC). The results revealed a yield of 96% of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole. The solvent was then distilled off from the filtrate, and the residual solid was crystallized using ethanol and then washed with ethanol to obtain 30.5 g of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole (yield, 87%; melting point, 79° to 81° C.).
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH2:22]1[O:33][C:32]2[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][C:24]=2[O:23]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:32]3[O:33][CH2:22][O:23][C:24]=3[CH:25]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: BrCCc1ccc2c(c1)OCO2
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc3c(c2)OCO3)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.3 g -see Preparation 8), 3,4-methylenedioxyphenethyl bromide (0.247 g -see Preparation 16), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 3 hours. The mixture was allowed to cool to room temperature, water (6 ml) was added and the mixture was extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a colourless foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield 0.27 g.