Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41].C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:37][O:38][CH2:39][C:40]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:34])([F:35])[F:36])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)=[O:41]
Reactant: COCC(=O)Cl
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4ccc(N5CCNCC5)nc4)cnn23)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COCC(=O)N1CCN(c2ccc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-{3-[7-(6-piperazin-1-ylpyridin-3-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea (20.5 mg, 0.0413 mmol) HCl salt, methoxyacetyl chloride (5.66 μL, 0.0619 mmol) and N,N-diisopropylethylamine (40.0 μL, 0.230 mmol) in DMSO (0.5 mL) was stirred at RT for 1 h. The mixture was diluted with DMSO, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=569.2.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:10][C:11]1[CH:12]=[C:13]([C:18](Cl)=[O:19])[C:14]([Cl:17])=[N:15][CH:16]=1>C(OCC)C>[Br:10][C:11]1[CH:12]=[C:13]([C:18]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=2[Cl:1])=[O:19])[C:14]([Cl:17])=[N:15][CH:16]=1
Reactant: Nc1cccc(Cl)c1Cl
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Solvent: CCOCC
Product: O=C(Nc1cccc(Cl)c1Cl)c1cc(Br)cnc1Cl
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of 2,3 dichloroaniline (3.875 g, 23.914 mmol) in diethyl ether (20 mL) was added 5-bromo-2-chloropyridine-3-carbonyl chloride (3.0 g, 11.96 mmol). The reaction was stirred overnight. The precipitated solids were collected and washed with diethyl ether to provide 3.6 g of 5-bromo-2-chloro-N-(2,3-dichlorophenyl)pyridine-3-carboxamide as a cream colored solid [LC-MS m/e=380.0 (M+H)]. Using the same procedure, 5-bromo-2-chloro-N-(2,3-fluorophenyl)pyridine-3-carboxamide and 5-bromo-2-chloro-N-(3-chloro-2-fluorophenyl)pyridine-3-carboxamide can be produced from reacting 5-bromo-2-chloropyridine-3-carbonyl chloride with 2,3 fluoroaniline and 3-chloro-2-fluoroaniline, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[C:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH:19]=[CH:18][C:17]4[CH:26]=[CH:27][CH:28]=[CH:29][C:16]3=4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>>[CH:25]1[C:20]2[CH:19]=[CH:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[C:15](=[C:12]3[CH2:11][CH2:10][N:9]([CH2:8][CH:7]=[CH:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:31][CH:30]=4)[CH2:14][CH2:13]3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Yield: 92 %

Procedure:
This compound was prepared from 1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) and pivaloyl chloride. Yield 92.0%
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH3:23]>FC(F)(F)C(O)=O.[Pt](=O)=O>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(N)nc3c(c2n1CCCCN)CCCC3
Reaction time: 144 h

Procedure:
A catalytic amount of platinum (IV) oxide was added to a solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (2.2 g, 7.06 mmol) in trifluoroacetic acid (200 mL). The reaction mixture was hydrogenated at 50 psi (3.44×105 Pa) on a Parr apparatus for 6 days. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum. The residue was combined with 1 N hydrochloric acid (100 mL) and heated on a steam bath for 2 hours. The mixture was cooled, made basic with ammonium hydroxide and then extracted with dichloromethane. The extract was concentrated under vacuum to provide of 1-(4-aminobutyl)-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 63-67° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH2:19])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:20][C:21]([F:27])([F:26])[S:22](Cl)(=[O:24])=[O:23]>>[F:20][C:21]([F:27])([F:26])[S:22]([NH:19][CH2:18][C:14]1[CH:15]=[N:16][CH:17]=[C:12]([C:7]2[N:8]([CH3:11])[C:9]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH:13]=1)(=[O:24])=[O:23]
Reactant: Cn1c(-c2cncc(CN)c2)cc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)C(F)(F)F
Product: Cn1c(-c2cncc(CNS(=O)(=O)C(F)(F)F)c2)cc2ccc(Cl)cc21

Procedure:
C-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine (Example 205a) and trifluoromethanesulfonyl chloride are processed according to the method described in Example 186f to give C,C,C-trifluoro-N-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide. 1H NMR (400 MHz, MeOD) δ ppm 3.80 (s, 3H), 4.59 (s, 2H), 6.72 (s, 1H), 7.12 (dd, J=8.5, 1.9 Hz, 1H), 7.54 (s, 1H), 7.60 (d, J=8.6 Hz, 1H), 8.05 (t, J=2.1 Hz, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 404.0443 [(M+H)+ Calcd for C16H14ClF3N3O2S: 404.0447].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][N:9]([C:11]([C:13]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=3[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:12])[CH2:8][C:5]2=[N:6][CH:7]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]3[CH2:10][N:9]([C:11]([C:13]4[CH:18]=[C:17]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:16]=[CH:15][C:14]=4[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:26])[F:27])=[O:12])[CH2:8][C:5]3=[N:6][CH:7]=2)=[CH:33][CH:32]=1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2cc(Br)cnc2C1)C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2cc(-c3ccc(F)cc3)cnc2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example 321 from (3-Bromo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (example 22) and 4-fluorophenyl boronic acid. White solid. MS (m/e): 509.2 [M+H]+, 100%).
Reaction SMILES: [CH2:1]([C:3]12[CH2:10][O:9][C:6]([C:11]3[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=3)([O:7][CH2:8]1)[O:5][CH2:4]2)[CH3:2].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C(NCC)C>[CH2:1]([C:3]12[CH2:10][O:9][C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:13][CH:12]=3)([O:7][CH2:8]1)[O:5][CH2:4]2)[CH3:2]
Reactant: CCC12COC(c3ccc(I)cc3)(OC1)OC2
Reactant: C#C[Si](C)(C)C
Solvent: CCNCC
Product: CCC12COC(c3ccc(C#C[Si](C)(C)C)cc3)(OC1)OC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Bis-triphenylphosphine palladium dichloride (60 mg) and cuprous iodide (10 mg) were added to a stirred solution of 4-ethyl-1-(4-iodophenyl)-2,6,7-trioxabicyclo[2,2,2]octane (1.5 gms) and trimethylsilylacetylene (0.92 ml) in dry diethylamine (40 ml) under nitrogen. The resulting mixture was stirred at room temperature for 16 hours. After this time the solvent was removed under vacuum and the residue extracted with diethylether. The ethereal solution was washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by column chromatography on alumina, eluting with 30% dichloromethane in hexane saturated with ammonia. 4-Ethyl-1-[4-(2-trimethylsilylethynyl)-phenyl]-2,6,7-trioxabicyclo[2,2,2]octane (1.2 gms) was obtained as an off-white solid (1.2 gms) after recrystallisation from hexane.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1
Reactant: Brc1ccccn1
Reactant: O=Cc1ccc(B(O)O)cc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccc(-c2ccccn2)cc1
Temperature: 77 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
A mixture of 4-formyl-phenylboronic acid (5.0 g, 33.0 mmol) and 2-bromopyridine (5.53 g, 35.0 mmol, 1.05 equiv.) in 265 mL of 4:3 toluene/95% ethanol was degassed with nitrogen for 30 minutes and then heated under a nitrogen atmosphere, resulting in a clear solution. A slurry of Pd(PPh3)4 (0.77 g) in 50 mL of a 4:4 mixture of toluene and 95% ethanol was added, followed by 50 mL of 3M aqueous Na2CO3. The resulting mixture was gently refluxed at 77° C. After 16 hours, the reaction mixture was cooled to room temperature, and the solid removed by filtration. The filtrate was transferred to a separatory funnel, and the layers separated. The aqueous layer was extracted with toluene (3×50 mL). The combined organics were washed with water, then saturated sodium chloride, and dried over sodium sulfate. The solution was filtered, and the filtrate concentrated under reduced pressure to give a yellow oil. Purification by Biotage chromatography (40+M cartridge; gradient, 0 to 5% methanol/dichloromethane) gave 4.13 g (68%) of (3) as a light-yellow solid. TLC Rf (hexane/ethyl acetate, 2:1)=0.25; 1H NMR (CDCl3) δ 10.1 (s, HCO), 8.77 (d, 1H), 8.20 (d, 2H), 8.00 (d, 2H), 7.81 (m, 2H), 7.31 (q, 1H); MS (M)+=184; HPLC tR 1.2 minutes.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:7][C:8]1[C:13]([CH2:14][OH:15])=[CH:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[C:10]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6].[CH3:33]I.O>CN(C)C=O>[CH2:3]([O:7][C:8]1[C:13]([CH2:14][O:15][CH3:33])=[CH:12][C:11]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[C:10]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1COC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (11 mg 4.5 mMol) is added to a stirring solution of 2-butoxy-6-(4-fluorophenyl)-3-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]pyridine (Example 29) (128 mg, 0.3 mMol) in dimethylformamide (50 mL). After 1 hour, methyl iodide (85 mg, 0.6 mMol) is added and the reaction mixture is stirred for 20 hours at room temperature. Water (1 mL) is added dropwise and the mixture is concentrated to an oily solid. The titled material is purified by silica gel chromatography.
Reaction SMILES: Br[CH:2]([C:11]([C:13]1[S:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[O:12])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C([O-])=[O:20].[Na+].CO>C(OCC)(=O)C>[Cl:18][C:15]1[S:14][C:13]([C:11](=[O:12])[CH:2]([OH:20])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:17][CH:16]=1
Reactant: O=C[O-]
Reactant: CCOC(=O)CCCC(Br)C(=O)c1ccc(Cl)s1
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCC(O)C(=O)c1ccc(Cl)s1

Procedure:
A mixture of ethyl 5-bromo-6-(5-chloro-2-thienyl)-6-oxohexanoate (64.4 g), sodium formate (60.0 g) and methanol (150 ml) was stirred with heating under reflux for 16 hours. The reaction mixture was diluted with ethyl acetate (500 ml) and washed with water (200 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 6-(5-chloro-2-thienyl)-5-hydroxy-6-oxohexanoate was obtained as a yellow oil (21.6 g, 41%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:7][CH2:6][C:5]2=[C:8]([NH2:11])[CH:9]=[N:10][N:4]2[CH2:3]1.Cl[C:14]1[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[CH:16][N:15]=1>CC(O)(C)C>[CH3:1][C:2]1([CH3:12])[O:7][CH2:6][C:5]2=[C:8]([NH:11][C:14]3[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:25])([F:23])[F:24])=[CH:16][N:15]=3)[CH:9]=[N:10][N:4]2[CH2:3]1
Reactant: CC1(C)Cn2ncc(N)c2CO1
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Solvent: CC(C)(C)O
Product: CNc1nc(Nc2cnn3c2COC(C)(C)C3)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 35.6 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with 6,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-amine (13 mg, 0.078 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (20 mg, 0.095 mmol), and t-BuOH (0.5 mL). The mixture was heated at 100° C. under microwave irradiation for 15 min. After concentration, the residue was purified by prep-HPLC to give the title compound (9.5 mg, 36%). 1H NMR (500 MHz, CDCl3) δ 8.09 (s, 1H), 7.67 (s, 1H), 6.79 (s, 1H), 5.18 (s, 1H), 4.83 (s, 2H), 3.93 (s, 2H), 3.00 (d, J=4.5 Hz, 3H), 1.63 (s, 6H). LC-MS (Method B): m/z=343.3 (M+H)+, 4.77 min, 98.2% purity.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[C:12]1[C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:14][S:15][N:16]=1.O>O1CCCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:12]1[C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:14][S:15][N:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-butoxyethanol (1.06 g, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH:1]1([C:4]([N:17]2[CH2:16][CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:19][CH2:18]2)=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Cyclopropanoyl chloride (112 μL) was added to a mixture of N-tert-butoxycarbonylpiperazine (200 mg) and an excess of potassium carbonate in anhydrous DCM (10 mL) under a nitrogen atmosphere. The mixture was stirred at r.t. for 18 hours, then it was filtered off from inorganics. The organic phase was diluted with Et2O (20 mL) and washed with 1N hydrochloric acid solution (10 mL). The aqueous phase was made basic with 1N sodium hydroxide solution and extracted twice with DCM. The combined organic layers were dried and concentrated in vacuo to give the title compound (210 mg) as an oil.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[N:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1.[BH4-].[Na+].C(OCC)(=O)C>C(O)C>[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:4][CH:1]2[CH2:3][CH2:2]2)=[CH:7][CH:6]=1
Reactant: O=Cc1ccncc1
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: c1cc(CNC2CC2)ccn1
Temperature: 90 °C
Reaction time: 24 h
Yield: 126.1 %

Procedure:
Cyclopropylamine (69 μL, 0.99 mmol) in ethanol (1 mL) was mixed with 4-pyridinecarbaldehyde (86 μL, 0.99 mmol) at room temperature and refluxed at 90° C. for 2 hours. After completion of the reaction, the ethanol was evaporated azeotropically. The resulting reaction product in methanol (1 mL) was mixed with sodium borohydride (204 mg, 5.40 mmol) under cooling with ice and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was mixed with ethyl acetate, and the organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired product (185 mg, quant.).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[CH2:20][CH:19]3[CH:15]([CH2:16][N:17]([C:21](=[O:37])[CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:18]3)[C:14]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[F:45])([OH:38])[CH2:13]2)(=O)=O)=CC=1.[C-:47]#[N:48].[K+]>>[C:47]([CH2:11][CH:12]1[CH2:20][CH:19]2[CH:15]([CH2:16][N:17]([C:21](=[O:37])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:18]2)[C:14]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])([OH:38])[CH2:13]1)#[N:48]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2CC3CN(C(=O)Cc4ccccc4OCc4ccccc4)CC3C(O)(c3ccccc3F)C2)cc1
Agent: [K+]
Product: N#CCC1CC2CN(C(=O)Cc3ccccc3OCc3ccccc3)CC2C(O)(c2ccccc2F)C1
Yield: 44 %

Procedure:
The procedure is as described for Example 13, starting from 1.67 g of (3aRS,4RS,6RS,7aSR)-6-p-toluenesulphonyloxymethyl-4-(2-fluorophenyl)-2-(2-benzyloxyphenylacetyl)perhydroisoindol-4-ol and 0.104 g of potassium cyanide, and gives 0.35 g of (3aRS,4RS,6SR,7aSR)-6-cyanomethyl-4-(2-fluorophenyl)-2-(2-benzyloxyphenylacetyl)perhydroisoindol-4-ol in the form of a thick pink foam.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:4][N:5]1[CH2:13][CH2:12][CH2:11][C@H:6]1[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:32][S:33]([O:1][CH2:2][C@@H:3]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH2:4][N:5]1[CH2:13][CH2:12][CH2:11][C@H:6]1[C:7]([O:9][CH3:10])=[O:8])(=[O:35])=[O:34]
Reactant: COC(=O)[C@@H]1CCCN1C[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C[C@@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Methyl 1-[(2S)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate (200 mg, 0.594 mmol) was dissolved in dichloromethane (5 mL) followed by the addition of 4-(dimethylamino)pyridine (3.6 mg, 0.039 mmol) and triethylamine (0.125 mL, 0.891 mmol) and the resulting mixture was cooled to 0° C. Methanesulfonyl chloride (0.060 mL, 0.773 mmol) was added dropwise and the reaction mixture was stirred for 1 h at 0° C. The mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford methyl 1-[(2S)-3-[(methylsulfonyl)oxy]-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate (246 mg, 100%) as a clear and colorless oil. MS (EI) for C18H27N2O7S: 415 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(O[CH2:20][C:21]1[CH:22]=[N:23][C:24]([Cl:27])=[CH:25][CH:26]=1)(=O)=O>>[Cl:27][C:24]1[N:23]=[CH:22][C:21]([CH2:20][O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)OCc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(Cl)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-42 using 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester and (6-chloropyridin-3-yl)methyl methanesulfonate; MS: 227 (M−100).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]=[CH:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:21](I)[CH3:22].O>CN(C)C=O>[CH2:21]([N:16]1[CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12][C:11]1=[N:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])[CH3:22]
Reactant: CCI
Reactant: CC(C)c1ccccc1N=C1N=CC(C)(C)CS1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CC(C)(C)CSC1=Nc1ccccc1C(C)C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a solution of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.26 g) in N,N-dimethylformamide (2 ml) was added under ice-cooling 60% sodium hydride (0.05 g). The mixture was stirred for 30 minutes. Ethyliodide (0.17 g) was added thereto. The mixture was stirred at room temperature for 2 hours. To a reaction mixture was added water (30 ml), extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 3-ethyl-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.21 g, yield: 71%) as colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12](Br)=[C:11]([N+:14]([O-:16])=[O:15])[C:10]([Br:17])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH2:19]>O>[CH2:1]([N:8]1[C:12]([NH:19][CH3:18])=[C:11]([N+:14]([O-:16])=[O:15])[C:10]([Br:17])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Br)nn(Cc2ccccc2)c1Br
Reactant: CN
Solvent: O
Product: CNc1c([N+](=O)[O-])c(Br)nn1Cc1ccccc1
Yield: 87 %

Procedure:
3.61 g (10 mmoles) of 1-benzyl -3,5-dibromo-4-nitropyrazole are heated in 100 ml of a 35-percent solution of methylamine in water for 4 hours at 60° C. After cooling, the separated precipitate is collected by filtration and recrystallized once from ethanol. 2.7 g (87 percent of theory) of 1-benzyl-3-bromo-5-methylamino-4-nitropyrazole are obtained in the form of colorless crystals with a melting point of 116° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:18]3[CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][C:14](=[O:21])[C:13]=3[C:12]([CH3:22])=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[C:18]3[CH2:17][C:16]([CH3:19])([CH3:20])[CH2:15][C:14](=[O:21])[C:13]=3[C:12]([CH3:22])=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1nn(-c2cccc([N+](=O)[O-])c2)c2c1C(=O)CC(C)(C)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(-c2cccc(N)c2)c2c1C(=O)CC(C)(C)C2
Temperature: 70 °C
Yield: 55.2 %

Procedure:
Stannous chloride dihydrate (0.94 g, 4.2 mmol) was added to a solution of 1-(3-nitrophenyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole (0.25 g, 0.84 mmol), prepared as described in example 3, in ethanol (5 ml). The reaction mixture was heated at 70° C. for about 1 hour, cooled to room temperature, poured onto ice, neutralized with 5% sodium bicarbonate and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel (cyclohexane:ethyl acetate=60:40) to give the title compound as a colourless solid (0.125 g, 60%): m.p. 131-132° C.