Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([OH:13])[CH:11]2[CH2:12][N:8]([CH2:9][CH2:10]2)[CH2:7]1)C.[NH2:15][NH2:16]>CO>[OH:13][C:6]1([CH2:5][C:4]([NH:15][NH2:16])=[O:3])[CH:11]2[CH2:12][N:8]([CH2:9][CH2:10]2)[CH2:7]1
Reactant: CCOC(=O)CC1(O)CN2CCC1C2
Reactant: NN
Solvent: CO
Product: NNC(=O)CC1(O)CN2CCC1C2
Reaction time: 8 h
Yield: 107 %

Procedure:
To a solution of the product of step (a) (1.12 g, 0.0056 moles) in methanol (20 ml) at room temperature was added anhydrous hydrazine (1.76 ml, 0.056 moles) and the mixture was stirred overnight. The mixture was concentrated in vacuo and azeotroped twice with toluene (100 ml) by heating to reflux in an apparatus fitted with a Dean-Stark trap to give the subtitle compound (1.11 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])(=[O:13])=[O:12].C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:37]([C:39]1[CH:55]=[CH:54][C:42]([CH2:43][C@@H:44]([C:46]([N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)=[O:47])[NH2:45])=[CH:41][CH:40]=1)#[N:38]>ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH:15]([C:19]([NH:45][C@H:44]([C:46]([N:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)=[O:47])[CH2:43][C:42]1[CH:41]=[CH:40][C:39]([C:37]#[N:38])=[CH:55][CH:54]=1)=[O:21])[CH:16]([CH3:18])[CH3:17])(=[O:13])=[O:12]
Reactant: N#Cc1ccc(C[C@H](N)C(=O)N2CCCCC2)cc1
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc2ccccc2c1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(NS(=O)(=O)c1ccc2ccccc2c1)C(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)N1CCCCC1
Reaction time: 1 h

Procedure:
To a suspension of 7 g (0.023 mole) of N-betanaphthylsulphonylvaline (III: R1 =CH(CH3)2 ; Ar=betanaphthyl) racemic (RS) in 10 ml of dichloromethane, kept at between 0° and +5° C., 2.6 g (0.023 mole) triethylamine is added, then 3.4 g (0.025 mole) of isobutyl chloroformate is added drop by drop, and the whole is left for one hour at this temperature. Then 6.2 g (0.024 mole) of 1-(p-cyanophenylalanyl)piperidine (II: NR2R3 =piperidino) dissolved in 50 ml of dichloromethane is added, and the reactional medium is left for 20 hours at ambient temperature. After evaporating to dryness, the residue is taken up with water. The aqueous phase is extracted with dichloromethane. The organic extracts are dried on anhydrous sodium sulphate and evaporated to dryness. The oily residue is purified by chromatography on a silica column (elution: toluene-ethyl acetate, 1:1).
Reaction SMILES: Cl.[C:2]1([C:12](=[NH:14])[NH2:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.O.[NH2:16]N.[C:18]([NH:21][CH:22]([CH2:30][CH3:31])[C:23](=O)[C:24](OCC)=[O:25])(=[O:20])[CH3:19]>CS(C)=O.C(O)C>[C:2]1([C:12]2[NH:13][C:24](=[O:25])[C:23]([CH:22]([NH:21][C:18](=[O:20])[CH3:19])[CH2:30][CH3:31])=[N:16][N:14]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)c1cccc2ccccc12
Reactant: CCOC(=O)C(=O)C(CC)NC(C)=O
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CS(C)=O
Product: CCC(NC(C)=O)c1nnc(-c2cccc3ccccc23)[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.0 g (4.84 mmol, 1 equiv.) 1-Naphthalenecarboximidamide hydrochloride are suspended in 2 ml of DMSO and 0.29 g (5.81 mmol, 1.2 equiv.) hydrazine hydrate are added. After stirring at room temperature for 16 hours, 1.45 g (7.3 mmol, 1.5 equiv.) of the compound of Example 2A, dissolved in 10 ml of ethanol, are added. The reaction mixture is stirred at reflux for 1 hour and then at 60° C. (bath temperature) for 4 hours and then at room temperature over night. The mixture is evaporated to dryness in vacuo and the product is purified by flash chromatography.
Reaction SMILES: O1CCCC1.[C:6]([C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=1)#[CH:7].[F:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[O:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[N:27][OH:28])=[CH:21][CH:20]=1.C(N(CC)CC)C>O>[F:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[O:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:26]2[CH:7]=[C:6]([C:8]3[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=3)[O:28][N:27]=2)=[CH:21][CH:20]=1
Reactant: ON=C(Cl)Cc1ccc(Oc2ccccc2F)nc1
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(Oc3ccccc3F)nc2)no1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
To a tetrahydrofuran (1 mL) solution of 3-ethynyl-pyridin-2-ylamine (9.0 mg, 0.076 mmol) described in Manufacturing Example 1-2-3 and (6-(2-fluoro-phenoxy)-pyridine-3-yl)-acetohydroximoyl chloride (28 mg) described in Manufacturing Example 74-1-4 was added triethylamine (21 μL, 0.15 mmol), which was stirred for 5 hours at 55° C. The mixture was cooled to room temperature and water was added at that temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound as a crude product. This was then purified by reverse-phase high-performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoracetic acid). Triethylamine was added to make the solvent basic when concentrating the mobile phase, and the eluate was concentrated under a reduced pressure. The resulting residue was washed with water to obtain the title compound (1.0 mg, 4%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=C(C#N)[C:7]=2[CH:6]=[CH:5]1)[CH3:3].[OH-:19].[Na+].[CH2:21]([OH:23])[CH3:22]>>[CH:2]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=[C:22]([C:21]([OH:19])=[O:23])[C:7]=2[CH:6]=[CH:5]1)([CH3:3])[CH3:1]
Reactant: CCO
Reactant: [OH-]
Reactant: CC(C)n1ccc2c(C#N)cc(C(F)(F)F)cc21
Agent: [Na+]
Product: CC(C)n1ccc2c(C(=O)O)cc(C(F)(F)F)cc21
Yield: 86 %

Procedure:
To a solution of 1-(1-methylethyl)-6-(trifluoromethyl)-1H-indole-4-carbonitrile (180 mg, 0.714 mmol) in ethanol (5 mL) was added 10% sodium hydroxide (5 mL, 0.714 mmol), and the mixture was heated at reflux overnight. The mixture was concentrated to remove EtOH and the aqueous phase was acidified using 1N HCl to ˜pH 4. The precipitate was collected by filtration and dried under high vacuum to give the title compound (167 mg, 86%) as brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.60 (m, 6H), 4.96-5.13 (m, 1H), 7.11 (d, J=3.28 Hz, 1H), 7.89-8.05 (m, 2H), 8.25 (s, 1H), 13.15 (br. s., 1H). MS: (M+H)+=272.0.
Reaction SMILES: Cl.C[O:3][C:4](=O)[C@H:5]([CH2:7][CH2:8][CH2:9][CH3:10])[NH2:6].CN1CCOCC1.[CH2:19]([O:26][C:27]([NH:29][C@H:30]([C:38]([OH:40])=O)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N=C=NCCCN(CC)CC)C>C(Cl)Cl.O>[CH:4]([CH:5]([NH:6][C:38](=[O:40])[C@H:30]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[NH:29][C:27]([O:26][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:28])[CH2:7][CH2:8][CH2:9][CH3:10])=[O:3]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCCC[C@H](N)C(=O)OC
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CCCCC(C=O)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 104.4 %

Procedure:
In 50 ml of methylene chloride was dissolved 1.8 g of L-norleucine methyl ester hydrochloride, and 1.1 ml of N-methylmorpholine was added to the solution. To the solution were further added 3.0 g of N-benzyloxycarbonyl-L-phenylalanine and 1.9 g of 1-ethyl-3-(3-diethylaminopropyl)carbodiimide, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a 10% citric acid solution, a saturated brine, a saturated sodium bicarbonate solution, and a saturated brine and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain 4.1 g of the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH:24]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:23][CH:24]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]([OH:30])[C:26]([F:27])([F:28])[F:29])=[O:22])[CH:15]=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:23][CH:24]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])=[O:21])[CH:15]=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(Cc1ccccc1)C(O)C(F)(F)F
Reactant: O=C(O)Cn1cncc(NC(=O)OCc2ccccc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cn1cncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(=O)C(F)(F)F
Product: O=C(Cn1cncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(O)C(F)(F)F

Procedure:
2-(5-Benzyloxycarbonylamino-6-oxo-1,6-dihydro-1-pyrimidyl)-N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)acetamide was synthesized in the same manner as in Example 1. That is, (5-benzyloxycarbonylamino-6-oxo-1,6-dihydro-1-pyrimidinyl)acetic acid (title compound in Reference Example 10, 1.20 g, 3.96 mmol) was treated with 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol (title compound in Reference Example 1, 911 mg, 4.16 mmol), WSCI hydrochloride (912 mg, 4.76 mmol) and HOBT (1.07 g, 7.92 mmol) in DMF (15 mL) to give 1.85 g (93%) of the target compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:12]([CH3:13])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:18]([O:11][C@@H:10]1[C@@H:12]([CH3:13])[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([F:1])[C:3]([NH2:17])=[N:4][C:5]2=[O:16])[C@@H:8]1[OH:9])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O)[C@@H]1O
Solvent: c1ccncc1
Product: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O)[C@@H]1OC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
5'-Deoxy-5-fluorocytidine (245 mg) was dissolved in dry pyridine (5 ml). To the solution was added benzoyl chloride (130 μl) with stirring at 0° C. The reaction mixture was stirred for 1 hour at 0° C. After removal of the solvent under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane - methanol) followed by recrystallization from ethyl acetate to give colorless crystals of 3'-O-benzoyl-5'-deoxy-5-fluorocytidine (51 mg). mp 127°~129° C.; MS 350 (MH+).
Reaction SMILES: CS(O[C@@H:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8])(=O)=O.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>CC#N>[CH3:10][O:9][C:7](=[O:8])[C@H:6]([NH:22][C:21]1[CH:23]=[CH:24][C:18]([F:17])=[CH:19][CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H](OS(C)(=O)=O)c1ccccc1
Reactant: Nc1ccc(F)cc1
Solvent: CC#N
Product: COC(=O)[C@H](Nc1ccc(F)cc1)c1ccccc1
Temperature: 120 °C
Yield: 94.2 %

Procedure:
To a solution of (S)-methyl 2-(methylsulfonyloxy)-2-phenylacetate (I5) (520 mg, 2.13 mmol) in CH3CN (10 mL), is added 4-fluoroaniline (473 mg, 4.26 mmol) and the mixture is heated at 120° C. for 5 minutes under MW irradiation (UPLC-MS: complete conversion). Acetonitrile was evaporated and the resulting crude is dissolved in 1N HCl and extracted several times with EtOAc. The combined organic phase is dried over Na2SO4, filtered and evaporated to dryness to obtain intermediate I254 as a pale yellow oil (520 mg, 94% yield).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Cl)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.67 ml benzylbromide are added dropwise to 1.73 g 3-hydroxy-4-chloro-benzoic acid and 3.04 g potassium carbonate in 10 ml N,N-dimethylformamide, and the reaction mixture is stirred overnight at ambient temperature. Then the reaction mixture is mixed with water and extracted with ethyl acetate. The combined organic phases are dried on magnesium sulphate and evaporated down. The flask residue is taken up in 5 ml of methanol, combined with 3 ml of 10 M aqueous potassium hydroxide solution and stirred for 4 h at 50° C. gerũhrt. The reddish solution is diluted with water and acidified with 3 N aqueous hydrochloric acid. The precipitate formed is suction filtered, washed with water and dried.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[N:17]3[CH:19]=[CH:20][CH:21]=[C:16]3[C:15](=O)[C:14]=2[CH:13]=[CH:12][CH:11]=1.Cl.[NH2:24][OH:25]>N1C=CC=CC=1>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[N:17]3[CH:19]=[CH:20][CH:21]=[C:16]3[C:15](=[N:24][OH:25])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: NO
Reactant: O=C1c2cccc(-c3nc4ccncc4[nH]3)c2-n2cccc21
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1c2cccc(-c3nc4ccncc4[nH]3)c2-n2cccc21
Yield: 81.3 %

Procedure:
In a 250 ml round-bottomed flask under argon, a mixture of 444 mg of 5-(3H-imidazo[4,5-c]pyridin-2-yl)pyrrolo[1,2-a]indol-9-one obtained according to the preceding stage and 323 mg of hydroxylamine hydrochloride in 60 ml of pyridine is refluxed for 3 hours. The reaction medium is evaporated to dryness under vacuum, the residue is taken up in a saturated solution of sodium bicarbonate and the precipitate is filtered off and washed with water. The solid is dissolved in methanol and the solvent is evaporated to dryness under vacuum. The residue is taken up in toluene and then re-evaporated to dryness under vacuum. 380 mg of 5-(3H-imidazo[4,5-c]pyridin-2-yl)pyrrolo[1,2-a]indol-9-one oxime are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][CH:25]=1>>[CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=3)=[CH:28][CH:29]=2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1
Reactant: CC(C)OCCOCc1ccc(OCC2CO2)cc1
Product: CC(C)OCCOCc1ccc(OCC(O)CNCCOc2ccc(C3=NNC(=O)CC3)cc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-((2-isopropoxyethoxy)methyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](=[O:29])[CH2:25]S(C)=O.N1CCCCC1>C1(C)C=CC=CC=1>[C:1]1([CH2:7][S:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]2[NH:17][C:18]3[C:19]([C:24](=[O:29])[CH:25]=2)=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)CC(=O)c1ccccc1N
Reactant: O=Cc1ccccc1SCc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=c1cc(-c2ccccc2SCc2ccccc2)[nH]c2ccccc12
Reaction time: 3 h
Yield: 55.3 %

Procedure:
2-[(Phenylmethyl)thio]benzaldehyde (2.28 g, 10 mmole, 1 equiv.), 1-(2-aminophenyl)-2-(methylsulfinyl)ethanone (1.97 g, 10 mmole, 1 equiv.), and piperidine (0.5 ml, 5 mole, 0.5 equiv.) were combined in toluene (50 ml), and the mixture was heated to reflux under a Dean-Stark trap. After 3 hr, the reaction was concentrated and the residue was chromatographed on silica gel (50% EtOAc/CHCl3) to afford 2-[2-[(phenylmethyl)thio]phenyl]-4(1H)-quinolinone (1.90 g, 55%) as a brownish-yellow foam. Recrystallization from CHCl3 /EtOAc gave light yellow crystals (1.39 g): mp 196°-197° C.; TLC (50% EtOAc/CHCl3) Rf 0.31; 1H NMR (CDCl3) δ8.63 (br s, 1H), 8.36 (dd, J=8.1, 0.8 Hz, 1H), 7.50-7.62 (m, 2H), 7.28-7.45 (m, 4H), 7.16-7.26 (m, 4H), 7.00-7.08 (m, 2H), 6.24 (d, J=1.8 Hz, 1H), 3.97 (s, 2H); IR (KBr) 2100-3200 (br), 1632, 1594, 1530, 1497, 1439 cm-1 ; MS (NH3), m/e (%) 344.1 (100, (M+H)+), 254.2 (26.9). Anal. Calcd for C22H17NOS: C, 76.54; H, 4.87; N, 3.91; S, 9.12. Found: C, 76.94; H, 4.99; N, 4.08; S, 9.34.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[C:26]#[N:27]>>[C:26]([C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[CH2:23][O:21][CH:9]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10]1)#[N:27]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Reactant: N#Cc1ccccc1CBr
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(OCc2ccccc2C#N)C1

Procedure:
In an analogous manner to that described in Example 9 (a)-(c), by alkylating tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 3 (b)] with 2-bromomethylbenzonitrile there was obtained tert-butyl (3RS,4RS)-3-(2-cyano-benzyloxy)-4-(4-fluoro-phenyl)-piperidine-1-carboxylate, reduction of which using borane-dimethyl sulphide complex gave tert-butyl (3RS,4RS)-3-(2-aminomethyl-benzyloxy)-4-(4-fluoro-phenyl)-piperidine-1-carboxylate. Subsequent acylation with pyridine-2-carboxylic acid in the presence of EDC yielded tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-(2-{[(pyridine-2-carbonyl)-amino]-methyl}-benzyloxy)-piperidine-1-carboxylate as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:26])[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(NC1C=CC(C(=O)CC2CCN(CC3C=CC=CC=3)CC=2)=CC=1)(=O)C>C(O)C.C1(C)C=CC=CC=1.[Pt]=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:26])[CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)C=C2CCN(Cc3ccccc3)CC2)cc1
Agent: O=[Pt]
Agent: CC(=O)Nc1ccc(C(=O)CC2=CCN(Cc3ccccc3)CC2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(C(=O)CC2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 5.5 h

Procedure:
In a mixed solution of 80 ml of ethanol and 30 ml of toluene was dissolved 7.10 g of the mixture of N-acetyl-4[(1-benzyl-4-piperidinyliden)acetyl]aniline and N-acetyl-4[(1-benzyl-1,2,5,6-tetrahydropyridin-4-yl)acetyl]aniline obtained in Reference example 14, and then 0.10 g of platinum oxide was added thereto. The mixture was stirred under a hydrogen stream for 5.5 hours. After the reaction, the catalyst was removed by filtration and condensed under reduced pressure. The residue obtained was applied to silica gel column chromatography to obtain 5.54 g of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:34])([F:33])[C:10]1[N:18]2[C:13]([CH:14]=[CH:15][C:16]([N:19]3[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[N:17]2)=[N:12][N:11]=1.C(=O)(O)[O-].[Na+]>ClCCl>[N:19]1([C:16]2[CH:15]=[CH:14][C:13]3=[N:12][N:11]=[C:10]([C:9]([F:8])([F:34])[F:33])[N:18]3[N:17]=2)[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.8 %

Procedure:
Trifluoroacetic acid (8 mL, 103.68 mmol) was added to a mixture of tert-butyl 4-[3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazin-6-yl]-1,4-diazepane-1-carboxylate (5.9 g, 15.3 mmol) and dichloromethane (80 mL) at ambient temperature and the resulting solution was stirred at ambient temperature for 6 hours. The reaction mixture was evaporated to give an involatile residue that was treated with saturated aqueous sodium bicarbonate solution (100 mL) and then extracted with dichloromethane (4×200 mL). The organic phases were combined and dried over Na2SO4, filtered, and evaporated to give 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazine (3.8 g, 86.9%) as a white solid. 1H NMR (300.132 MHz, DMSO) δ 1.68-1.84 (m, 2H), 2.69 (t, 2H), 2.88 (t, 2H), 3.60-3.79 (m, 4H), 7.46 (d, 1H), 8.19 (d, 1H); m/z. 287 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[NH:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[C:11]([C:21](=O)[CH3:22])=[CH:12][C:13]([Cl:20])=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:6]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+].O1CCCC1>CO.C(#N)C>[CH3:1][O:2][C:3](=[O:24])[NH:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[C:11]([CH:21]([NH2:31])[CH3:22])=[CH:12][C:13]([Cl:20])=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:6]1
Reactant: [BH3-]C#N
Reactant: COC(=O)N[C@H]1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: COC(=O)N[C@H]1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)C1
Temperature: 65 °C

Procedure:
A mixture of methyl[(3S)-1-(7-acetyl-5-chloroquinolin-8-yl)pyrrolidin-3-yl]carbamate (0.047 g, 0.14 mmol) and ammonium acetate (0.104 g, 1.35 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.34 mL, 0.34 mmol). The reaction was heated at 65° C. overnight. The mixture was then cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C17H22ClN4O2 (M+H)+: m/z=349.1; Found: 349.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:22][CH3:23])[C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11].C([Li])CCC.[CH:29](N1CCOCC1)=[O:30].Cl>C1COCC1.C(OCC)(=O)C>[CH3:23][O:22][C:4]1[CH:3]=[C:2]([CH:19]=[C:6]([CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])[C:5]=1[O:20][CH3:21])[CH:29]=[O:30]
Reactant: COc1cc(Br)cc(CO[Si](C(C)C)(C(C)C)C(C)C)c1OC
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C=O)cc(CO[Si](C(C)C)(C(C)C)C(C)C)c1OC
Reaction time: 0.25 h

Procedure:
To a solution of the 3.616 g of (5-bromo-2,3-dimethoxybenzyloxy)triisopropylsilane in 60 ml of THF there was added dropwise 3.6 ml of n-butyllithium (2.66 M, hexane solution) at −78° C. under a nitrogen atmosphere. After stirring for 15 minutes, 2 ml of N-formylmorpholine was added and the mixture was stirred at room temperature for 20 minutes. Next, 1N hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (2.605 g) as an oil.