Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[C:17]([NH2:18])=[C:16]([NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=[CH:34][CH:33]=1.C(Cl)(=O)C>C(OCC)(=O)C>[CH3:33][C:34]1[N:19]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:16]2[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:17]=2[N:18]=1
Reactant: Nc1c(Oc2ccccc2)nc2c(c1NCCOCCCc1cccnc1)CCCC2
Reactant: c1ccncc1
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: Cc1nc2c(Oc3ccccc3)nc3c(c2n1CCOCCCc1cccnc1)CCCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A 200 ml round bottom flask was charged with 2-phenoxy-N4-[2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinoline-3,4-diamine (4.1 g, 0.0098 mol.) and pyridine (40 mL) at room temperature. To this solution was slowly added acetyl chloride (0.8 g, 0.011 mol., 1.1 equivalents). The reaction was maintained with stirring at room temperature. After two hours the reaction was monitored and found to only contain the amide intermediate. The reaction mixture was then heated to reflux and maintained overnight. The reaction mixture was concentrated to provide a dark amber syrup. The syrup was taken up in ethyl acetate (300 mL) and washed with water (2×100 mL). The ethyl acetate layer was concentrated to provide 2-methyl-4-phenoxy-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline as an orange syrup (3.8 g, 88%). TLC (10%MeOH/CH2Cl2, Rf=0.34). Mass-spec M+1=443.2
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([C:36]#[N:37])=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>C(#N)C>[C:36]([C:30]1[CH:29]=[C:28]2[C:33]([C:24]([O:23][C:22]3[CH:38]=[CH:39][C:19]([NH:18][C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)=[O:17])=[CH:20][CH:21]=3)=[CH:25][CH:26]=[N:27]2)=[CH:32][C:31]=1[O:34][CH3:35])#[N:37]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1cc2c(Oc3ccc(N)cc3)ccnc2cc1C#N
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1C#N

Procedure:
After adding toluene (5 ml), acetonitrile (1.5 ml) and 4-fluorophenyl isocyanate (0.105 ml) to 4-(4-aminophenoxy)-6-methoxyquinoline-7-carbonitrile (180 mg), the mixture was heated to reflux for 30 minutes. The mixture was cooled, and the precipitated crystals were filtered out and washed with toluene to obtain the title compound (230 mg) as light yellow crystals.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:18][CH2:19][C:20](Cl)=[O:21].O>CC(C)=O.O>[Cl:18][CH2:19][C:20]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1NC(=O)CCl
Reaction time: 2 h

Procedure:
38 Grams of methyl anthranilate and 35 g of potassium carbonate were dissolved in 300 ml of a mixture of acetone-water (2:1), then to this solution was added dropwise 30 g of chloroacetyl chloride under an ice-cooled condition with stirring. After completion of the addition, the reaction was carried out at a room temperature for 2 hours, then 200 ml of water was added to the reaction mixture, and the mixture obtained was ice-cooled, and the crystals precipitated were collected by filtration. The crystals collected were washed with water and ethanol, and recrystallized from methanol to obtain 48.6 g of methyl o-(α-chloroacetylamino)benzoate in the form of colorless needle-like crystals. Melting point: 97°-99° C.
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([S:21]([C:24]4[S:28][C:27]5[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:26]=5[CH:25]=4)(=[O:23])=[O:22])[CH2:17][C:16]3=[O:34])=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1)=[N+]=[N-]>C(O)(=O)C.CO.[Pd]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([S:21]([C:24]4[S:28][C:27]5[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:26]=5[CH:25]=4)(=[O:22])=[O:23])[CH2:17][C:16]3=[O:34])=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1
Reactant: [N-]=[N+]=Nc1ccnc2cc(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)ccc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccnc2cc(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)ccc12
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
A suspension of 1-(4-azidoquinolin-7-ylmethyl)-4-(6-chlorobenzo[b]thiophen-2-sulfonyl)-piperazin-2-one (0.50 g, 1.04 mmol) in 100 mL of acetic acid/methanol (˜1:10) is treated with 10% Pd/C (0.15 g) and stirred under hydrogen for 1.5 hours. The resulting solution is filtered through Celite and the filtrate is evaporated in vacuo. The organic layer is concentrated and the residue is purified by reverse phase HPLC (gradient elution of 30% of 0.1% aqueous TFA/acetonitrile to 100% acetonitrile) and lyopholized to give the title compound (0.39 g, 0.86 mmol). MS (ISP) m/z 487, 489, (M+H), Cl pattern.
Reaction SMILES: C(N(C[C:7]1[CH:12]=[C:11]([C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH3:14])[CH:10]=[C:9]([C:22]2[C:30]3[N:29]=[N:28][NH:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)[C:8]=1[OH:31])CC)C>C1(C)C(C)=CC=CC=1>[C:13]([C:11]1[CH:10]=[C:9]([C:22]2[C:30]3[N:29]=[N:28][NH:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)[C:8]([OH:31])=[CH:7][CH:12]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:15])[CH3:14]
Reactant: CCN(CC)Cc1cc(C(C)(C)c2ccccc2)cc(-c2cccc3[nH]nnc23)c1O
Solvent: Cc1ccccc1C
Product: CC(C)(c1ccccc1)c1ccc(O)c(-c2cccc3[nH]nnc23)c1

Procedure:
The xylene solution was prepared in the same manner as in Synthesis Example (10) except that there were used 10.0 g of 2-diethylaminomethyl-4-cumyl-6-benzotriazolylphenol or a Mannich base compound, which had been obtained in the same manner as in Synthesis Example (10), except that 4-cumyl-6-benzotriazolylphenol was used as the main material for the Mannich base compound, and 6.6 g of 4-cumyl-6-benzotriazolylphenol. The resulting solution was allowed to react in the same manner as in Synthesis Example (10) and subjected to the same treatment as in Synthesis Example (10) to obtain an opal crystal having a melting point of 191° C. (the intended product).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:31][CH2:30][CH2:29][NH:28]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[C:13]([F:26])[CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>>[C:32]([N:28]1[CH2:29][CH2:30][CH2:31][C@H:27]1[C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[C:13]([F:26])[CH:12]=2)[N:9]=1)(=[O:35])[CH:33]=[CH2:34]
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)c(F)c3)c12
Reactant: C=CC(=O)Cl
Product: C=CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)c(F)c2)c2c(N)nccn12
Yield: 38.4 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 1, from (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluoro-N-(pyridin-2-yl)benzamide (intermediate 17) and acryloylchloride, to afford the title compound (13 mg, 38.4%). Data: UPLC (C) Rt: 1.67 min; m/z 472.3 (M+H)+.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H][H]>[Pd].CO>[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Fc1cccc(C2=CCCN(Cc3ccccc3)C2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Fc1cccc(C2CCCNC2)c1
Yield: 100 %

Procedure:
A mixture of 6.5 parts of 5-(3-fluorophenyl)-1,2,3,6-tetrahydro-1-(phenylmethyl)pyridine hydrochloride and 120 parts of methanol was hydrogenated at normal pressure and at 50° C. with 1 part of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 4.5 parts (100%) of 3-(3-fluorophenyl)piperidine hydrochloride as a residue (intermediate 93).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.[CH3:13][NH:14][NH2:15].Cl.O>CCCCO>[CH3:13][N:14]1[C:2]2=[C:3]3[CH:12]=[CH:11][NH:10][C:4]3=[N:5][CH:6]=[C:7]2[CH:8]=[N:15]1
Reactant: O=Cc1cnc2[nH]ccc2c1Cl
Reactant: CNN
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: Cn1ncc2cnc3[nH]ccc3c21
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (1.37 g, 7.59 mmol, Adesis) and methylhydrazine (0.599 mL, 11.4 mmol) in n-BuOH (7 mL) were heated to about 95° C. After about 15 min, concentrated HCl (0.500 mL, 16.4 mmol) was added and the reaction mixture was heated to about 120° C. After about 4 h, water (10 mL) was added and the mixture was extracted with EtOAc (20 mL). The organic layer was separated and the aqueous layer was basified with saturated aqueous NaHCO3 to about pH 8 and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g column) eluting with a gradient of 5-60% EtOAc in heptane to give 1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.960 g, 74%): LC/MS (Table 2, Method d) Rt=1.40 min; MS m/z: 173 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.O.[OH-].[Na+].Cl>C(O)C>[C:15]1([C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:7]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:6][CH2:5][OH:4])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)OCCC(=C(c1ccccc1)c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCC(=C(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
34.2 g of 4-acetoxy-1,1,2-triphenyl-1-butene are dissolved in 200 ml of 94% ethanol, after which 20 ml of water and 45 ml of a 20% sodium hydroxide solution are added. The mixture is refluxed for 1 h. The solution is neutralized with 2M hydrochloric acid, after which the ethanol is evaporated. Water is added into the residue. The product is extracted in ethyl acetate, the ethyl acetate solution is dried over sodium sulfate and the solvent is evaporated. The product is recrystallized from a mixture of water and methanol and then has m.p. 117°-9° C. The yield is 23.7 g (79%).
Reaction SMILES: [CH2:1]([N:8]([CH2:15][Si](C)(C)C)[CH2:9]OCCCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([NH:27][C:28]1([C:31]#[C:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:30][CH2:29]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:9][C:31]([C:28]2([NH:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:30][CH2:29]2)=[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C#CC1(NC(=O)OC(C)(C)C)CC1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1=C(C2(NC(=O)OC(C)(C)C)CC2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
N-Benzyl-N-(n-butoxymethyl)trimethylsilylmethylamine (2.006 g, 7.176 mmol) and ethyl 3-(1-tert-butoxycarbonylaminocyclopropyl)propiolate (1.136 g, 4.485 mmol) were dissolved in dry dichloromethane (9 ml) and, while stirring at room temperature, the solution was mixed with dichloromethane solution of 1.0 M trifluoroacetic acid (0.72 ml, 0.72 mmol). After 3 hours of stirring, the reaction solution was mixed with a saturated sodium bicarbonate aqueous solution (20 ml) and extracted with dichloromethane (20 ml×3). The organic layers were combined, washed with saturated brine (30 ml) and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was applied to a flash silica gel chromatography column and eluted with chloroform, to thereby obtain 1.449 g (83.6%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:17]=23)[CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C.[S:38](Cl)([CH3:41])(=[O:40])=[O:39]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24]([CH:25]4[CH2:26][CH2:27][N:28]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:29][CH2:30]4)[C:17]=23)[CH:12]=[CH:11][N:10]=1
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4cnn(C5CCNCC5)c34)ccn2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cnn(C5CCN(S(C)(=O)=O)CC5)c34)ccn2)c1
Temperature: 25 °C
Yield: 19.8 %

Procedure:
N-(2-(2-Fluoro-5-methylphenyl)pyridin-4-yl)-1-(piperidin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (17 mg, 0.042 mmol) and triethylamine (0.018 ml, 0.127 mmol) were combined in dichloromethane (3 mL) and cool in an ice bath. Mesyl chloride (3.61 μl, 0.046 mmol) was added and the reaction was briefly warmed to room temperature. The reaction mixture was concentrated and purified by silica column chromatography eluting with 0-5% methanol in dichloromethane to give to afford N-(2-(2-fluoro-5-methylphenyl)pyridin-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (4 mg, 20%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.93 (d, J=10.61 Hz, 2H) 2.24-2.43 (m, 5H) 2.55-2.69 (m, 2H) 2.76 (s, 3H) 3.84 (d, J=12.63 Hz, 2H) 4.57 (t, J=10.74 Hz, 1H) 6.29 (br. s., 1H) 6.60 (dd, J=5.56, 2.02 Hz, 1H) 6.88-7.09 (m, 1H) 7.09-7.25 (m, 3H) 7.75 (dd, J=7.45, 2.15 Hz, 1H) 8.33 (s, 1H) 8.50 (d, J=5.56 Hz, 1H) 8.56 (d, J=4.55 Hz, 1H). MS [M+H] found 481.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][N:21]([CH2:23][CH2:24]Cl)[CH3:22]>CC(C)=O.O>[CH3:20][N:21]([CH2:23][CH2:24][O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:22]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1OCCN(C)C
Yield: 69.9 %

Procedure:
A stirred solution of 2-methoxy-5-nitrophenol (5.0 g, 0.029 mole) and potassium carbonate (8.3 g, 0.060 mole) in acetone (200 ml) and water (60 ml) was treated with N,N-dimethylaminoethyl chloride hydrochloride (8.64 g, 0.060 mole) and heated under reflux for 10 h. The mixture was concentrated under vacuum to approx. 80 ml volume, then acidified with 2M HCl acid (150 ml) and washed with ethyl acetate (2×80 ml). The acid solution was basified with K2CO3 and extracted with ethyl acetate (2×100 ml). The combined extract was dried (Na2 SO4) and concentrated under vacuum to afford the title compound as a yellow solid (4.87 g, 70%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[S:8](=[O:13])(=[O:12])[N:7]=[CH:6][NH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH3:21]>C(#N)C.O>[CH2:20]([N:5]1[C:4]2[CH:3]=[C:2]([CH3:1])[CH:11]=[N:10][C:9]=2[S:8](=[O:13])(=[O:12])[N:7]=[CH:6]1)[CH3:21]
Reactant: CCBr
Reactant: Cc1cnc2c(c1)NC=NS2(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN1C=NS(=O)(=O)c2ncc(C)cc21

Procedure:
A solution of 1.2 g of 6-methyl-4H-pyrido[3,2-e][1,2,4]thiadiazine 1,1-dioxide (Example 75) in 15 cm3 of acetonitrile is treated with 2.5 g of potassium carbonate and 2 g of ethyl bromide. After refluxing for 16 hours, the solvent is removed under partial vacuum and the solid obtained is taken up in 15 cm3 of water. The precipitate is collected on a filter, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[S:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24](O)=[O:25])=[CH:23][C:18]=2[N:17]=[N:16]1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24]([C:22]2[CH:21]=[CH:20][C:19]3[S:15][N:16]=[N:17][C:18]=3[CH:23]=2)=[O:25])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc2snnc2c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc2snnc2c1

Procedure:
50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to benzo-1,2,3-thiadiazole-5-carboxylic acid via Procedure G. The crude product was purified via reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)benzo[d][1,2,3]thiadiazole-5-carboxamide. MS (Q1) 367 (M)+.
Reaction SMILES: [F:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].CO.OO>C1COCC1>[F:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)C(F)C1
Temperature: 0 °C

Procedure:
A solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate, 2.3 (80 g, 0.368 mol) in THF (800 mL) was treated with L-Selectride (405 mL, 0.405 mol, drop wise) at −78° C. under nitrogen atmosphere. The resulting reaction mixture was stirred for 30 min. at the same temperature, MeOH (45.1 mL, 1.105 mol) 1M NaOH (1104 mL, 1.105 mol) were added and the reaction was allowed to warm to 0° C. The reaction was quenched by drop wise addition of H2O2 (125.1 mL, 1.843 mol). The volatiles were removed under vacuume and diluted with water (500 mL) and methylene chloride (500 mL). After separation, the organic layer was washed brine, dried over Na2SO4 and concentrated in vacuum to provide the desired product tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate, 2.4 (63 g, 78%). 1HNMR (CDCl3, 400 MHz): δ 4.70-4.65 (m, 0.5H), 4.58-4.52 (m, 0.5H), 3.99-3.84 (m, 2H), 3.82-3.58 (m, 1H), 3.55-3.27 (m, 1H), 3.18 (brs, 1H), 2.06 (brs, 1H), 1.89-1.70 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: Cl.C[O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.C(N(CC)C(C)C)(C)C.[NH2:21][NH2:22]>C(O)C>[NH:9]1[CH:10]=[C:6]([CH2:5][C:4]([NH:21][NH2:22])=[O:3])[N:7]=[CH:8]1
Reactant: NN
Reactant: COC(=O)Cc1c[nH]cn1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NNC(=O)Cc1c[nH]cn1
Temperature: 70 °C

Procedure:
To a solution of 4-imidazoleacetic acid methyl ester hydrochloride (3.95 g, 22.4 mmol) in ethanol (150 ml) is added N,N-diisopropylethylamine (2.90 g, 16.6 mmol) and hydrazine (1.79 g, 36 mmol). The solution is refluxed at 70° C. overnight. The solution is concentrated and recrystallized from methanol to give 4-imidazoleacetic acid hydrazide as a white solid. The yield is 2.46 g, 78%.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]([CH2:22][CH2:23]OS(C)(=O)=O)([CH2:15][CH2:16]OS(C)(=O)=O)[C:12](=[O:14])[N:13]=1.[CH:29]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30]1.CO>C(Cl)Cl>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]2([CH2:22][CH2:23][N:34]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:16][CH2:15]2)[C:12](=[O:14])[N:13]=1
Reactant: CS(=O)(=O)OCCC1(CCOS(C)(=O)=O)SC(NC2CC3CCC2C3)=NC1=O
Reactant: NC1CCCC1
Solvent: CO
Solvent: ClCCl
Product: O=C1N=C(NC2CC3CCC2C3)SC12CCN(C1CCCC1)CC2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of methanesulfonic acid 2-[2-(bicyclo[2.2.1]hept-2-ylamino)-5-(2-methanesulfonyloxy-ethyl)-4-oxo-4,5-dihydro-thiazol-5-yl]-ethyl ester (half of the crude product from above) and cyclopentylamine (799 mg, 9.38 mmol) in CH2Cl2 (1.5 mL) was stirred at room temperature for 4 d. Flash column chromatography (silica gel, 0-10% MeOH in CH2Cl2) afforded the title compound as an off-white solid (52 mg). MS (ESI, pos. ion) m/z: 348 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)=[O:32])=[N:28][CH:29]=1>O1CCCC1>[CH:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:41]=[CH:42][C:33]=1[C:31]([NH:30][C:27]1[N:28]=[CH:29][C:24]([CH2:23][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]2)=[CH:25][CH:26]=1)=[O:32]
Reactant: O=C(Nc1ccc(CBr)cn1)c1ccc2ccccc2c1
Reactant: CCOC(=O)Cc1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)nc2)c2ccccc12
Temperature: 25 °C
Yield: 21.3 %

Procedure:
Ethyl 2-(1H-indazol-3-yl)acetate (320 mg, 1.57 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). Cesium carbonate (1.53 g, 4.70 mmol) was added, and stirred at room temperature for half an hour. Then N-[5-(bromomethyl)pyridin-2-yl]-2-naphthamide (532 mg, 1.56 mmol) was added. After reacted for 16 hours, the solid was filtered. The filtrate was concentrated, chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a light yellow solid 154 mg, at a yield of 21.2%.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:7]([O:9]CC)=O)=[CH:5][N:6]=1.[NH3:12]>CO>[Cl:1][C:2]1[S:3][C:4]([C:7]([NH2:12])=[O:9])=[CH:5][N:6]=1
Reactant: CCOC(=O)c1cnc(Cl)s1
Reactant: N
Solvent: CO
Product: NC(=O)c1cnc(Cl)s1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Dissolve ethyl 2-chlorothiazole-5-carboxylate (0.927 g, 4.84 mmol) in methanol. Cool the solution to 0° C., then bubble NH3 into the reaction mixture for 10 minutes. Then seal the reaction vessel and stir for 3 hours. Concentrate the reaction mixture to give the title product: 1H NMR (CDCl3): 8.21 (s, 1H), 8.19 (s, 1H), 7.77 (s, 1H); HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=6.9 min, 100% purity.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][C:25]1([CH3:31])[O:29][C:28](=[O:30])[NH:27][CH2:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[N:7][C:2]([N:27]4[CH2:26][C:25]([CH3:31])([CH3:24])[O:29][C:28]4=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC1(C)CNC(=O)O1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)nn3)CC2)c(C)c1
Yield: 43.7 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 230 and 5,5-dimethyloxazolidin-2-one (63 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (81 mg) was obtained.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].[Cl:7][CH2:8][CH2:9][C:10](Cl)=[O:11]>C(#N)C>[Cl:7][CH2:8][CH2:9][C:10]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])=[O:11]
Reactant: O=C(Cl)CCCl
Reactant: COC(=O)NN
Solvent: CC#N
Product: COC(=O)NNC(=O)CCCl
Reaction time: 16 h
Yield: 78.3 %

Procedure:
To a solution of 45 g. (0.5 moles) of methyl carbazate in 375 ml. of acetonitrile 63.5 g. (0.5 moles) of 3-chloro-propionyl chloride are added dropwise. The reaction mixture is heated to boiling for 16 hours, clarified and cooled. The precipitated crystals are filtered. Thus 70.5 g. of the desired compound are obtained in the form of white crystals. Yield: 78.3%. M.p.: 129° C.