Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[F:26])[C@H:12]([CH3:18])[CH2:13][CH2:14][N:15]=[N+]=[N-])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[F:26])[C@H:12]([CH3:18])[CH2:13][CH2:14][NH2:15])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C[C@H](CCN=[N+]=[N-])N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CCN)N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of 4-chloro-N-(5-chloro-2-fluorophenyl)-N-[(R)-1-methyl-3-azidopropyl]-benzenesulfonamide (1.34 g, 3.27 mmol) in THF (32 mL) was added lithium aluminum hydride (6.53 mL, 1 M in THF) at 0° C. under nitrogen atmosphere. The resulting mixture was allowed to stir at 0° C. for 1 h and subsequently treated by successive dropwise addition of 0.248 mL of water, 0.248 mL of 15% sodium hydroxide solution, and 0.744 mL of water. The mixture was filtered and concentrated under reduced pressure. Silica gel chromatography (3:10 ethyl acetate:hexanes) of the concentrate afforded 1.12 g of 4-chloro-N-(5-chloro-2-fluorophenyl)-N-[(R)-1-methyl-3-aminopropyl]benzenesulfonamide as a light brown oil in 85% yield.
Reaction SMILES: [CH2:1]([CH:3]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH:5]([CH3:8])[CH2:6][CH3:7])[CH3:2].Br[CH2:17][CH2:18][CH3:19]>>[CH2:1]([CH:3]([N:9]([CH2:17][CH2:18][CH3:19])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:4][CH:5]([CH3:8])[CH2:6][CH3:7])[CH3:2]
Reactant: CCC(C)CC(CC)Nc1ccccc1
Reactant: CCCBr
Product: CCCN(c1ccccc1)C(CC)CC(C)CC

Procedure:
N-(1-Ethyl-3-methylpentyl)-N-propylaniline was prepared from N-(1-ethyl-3-methylpentyl)aniline and 1-bromopropane using the same method as in Example 2ii).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=2)[CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:22]=2[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:13]=1)=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[CH2:41]([O:40][C:38]([CH2:37][CH2:36][C:22]1[C:23]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:12]1[CH:13]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[C:10]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=2)[CH:11]=1)=[O:39])[CH3:42]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)OC(C)(C)C)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
5-{6-[2-(2-Ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-3′-fluoro-biphenyl-3-carboxylic acid tert-butyl ester (7.0 g) was dissolved in a mixture of TFA and dichloromethane (1:1, 80 mL) and stirred at room temperature for 1 h. The solvents were removed under reduced pressure and the crude material was purified on a silica gel column using ethyl acetate and hexanes to yield the title compound (5.9 g, 90% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])(=[O:3])[CH3:2].S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O.[N+:30]([O-])([OH:32])=[O:31]>>[C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][C:15]=1[N+:30]([O-:32])=[O:31])[NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(NC(=O)C(C)C)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CC(=O)c1cc(NC(=O)C(C)C)ccc1[N+](=O)[O-]
Temperature: -8 °C
Reaction time: 0.67 h

Procedure:
Add portion-wise 16.4 g. of m-acetyl-isobutyranilide to a solution of 44 milliliters of concentrated sulfuric acid and 62 milliliters of oleum (30-33%) while maintaining the internal temperature at 0°-5° C. Cool the mixture to -8° C. and add drop-wise 65 milliliters of 90% nitric acid. Stir the reaction mixture at 0°-5° C. for an additional 40 minutes and precipitate the product as described in Example 1 to obtain 3'-acetyl-4'-nitro-isobutyranilide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[N+]([O-])=O)\[CH3:10])=[CH:4][C:3]=1[N+:14]([O-])=O.C(O)(=[O:19])C>[Fe]>[NH2:14][C:3]1[CH:4]=[C:5]([CH2:8][C:9](=[O:19])[CH3:10])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: C/C(=C\c1ccc(Cl)c([N+](=O)[O-])c1)[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Fe]
Product: CC(=O)Cc1ccc(Cl)c(N)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 1-Chloro-2-nitro-4-((E)-2-nitro-propenyl)-benzene (13.6 g, 56 mmol) in glacial acetic acid (100 ml) is added slowly to a stirred slurry of Iron powder (34 g, 610 mmol) in glacial acetic acid (100 ml) at 60° C. The reaction mixture is stirred at 60° C. for 1 hour then allowed to cool to room temperature and stirred overnight. The reaction mixture is poured onto ice-water (300 ml) and filtered through Celite® (filter agent) washing with DCM (500 ml). The organic portion is separated and washed with water (2×300 ml) and brine (300 ml), dried over MgSO4, filtered and concentrated in vacuo to give a brown oil. The crude residue is absorbed onto silica and purification by flash chromatography on silica eluting with 20% EtOAc/Hexanes affords the title compound.
Reaction SMILES: O.[OH-].[Li+].[C:4]1([C@H:10]2[O:16][C@H:11]2[C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.CO>[C:4]1([C@H:10]2[O:16][C@H:11]2[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H]1O[C@@H]1c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1O[C@@H]1c1ccccc1
Reaction time: 1 h
Yield: 80.5 %

Procedure:
Under ice cooling, a solution of 0.504 g of lithium hydroxide monohydrate dissolved in 25 ml of water was added dropwise to a solution of 1.78 g of methyl (2R,3R)-3-phenyl-2,3-epoxypropionate dissolved in 50 ml of methanol. The mixture was allowed to room temperature and stirred for 1 hour at the same temperature. Methanol was removed from the reaction mixture, and the pH of the residue was adjusted to 3 to 4 by adding a 5% aqueous citric acid solution thereto under ice cooling, and then extracted with chloroform. The chloroform layer was washed with brine and then dried over magnesium sulfate. The solvent was removed under reduced pressure, and hexane was added to the residue. Crystals precipitated were collected by filtration, washed with hexane and then dried to obtain 1.32 g of (2R,3R)-3-phenyl-2,3-epoxypropionic acid. Yield: 80%
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[Si:5]([O:12][C@@H:13]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1)[C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][OH:16])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].N1C=CC=CC=1>CC#N.C(Cl)Cl.C1COCC1>[Si:5]([O:12][C@@H:13]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=1)[C@H:14]1[CH2:15][O:16][S:1](=[O:2])[N:17]1[C:18]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])([C:8]([CH3:9])([CH3:10])[CH3:11])([CH3:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C(F)(F)F)cc2)COS1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
To a solution of thionyl chloride (0.74 mL, 10.1 mmol) in MeCN (12 mL) and DCM (12 mL) at −78° C. was added a solution of tert-butyl (1S,2R)-1-(tert-butyldimethylsilyloxy)-3-hydroxy-1-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (1.82 g, 4.05 mmol) in MeCN (20 mL), DCM (20 mL) and THF (4 mL) dropwise via a dropping funnel. After 10 minutes, pyridine (1.82 mL, 22.3 mmol) was added dropwise at −78° C. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed in vacuo. The residue was taken up in EtOAc (60 mL), washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0%-10% EtOAc-hexane) to provide the product as a white solid (1.80 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:33])([C:31]#[CH:32])[CH3:30])=[N:27][CH:28]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:32]#[C:31][C:29]([C:26]4[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=4)([OH:33])[CH3:30])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(O)c1ccc(Cl)cn1
Reactant: Nc1nccc(-n2c(OCCO)nc3ccc(Br)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(O)(C#Cc1ccc2nc(OCCO)n(-c3ccnc(N)n3)c2c1)c1ccc(Cl)cn1
Temperature: 25 °C
Yield: 0.8 %

Procedure:
A solution of 2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol (200 mg, 0.57 mmol), 2-(5-chloropyridin-2-yl)but-3-yn-2-ol (518 mg, 2.85 mmol), bis(triphenylphosphine)palladium(II) dichloride (400 mg, 0.57 mmol) and triethylamine (0.5 mL) in DMSO (0.5 mL) was irradiated under nitrogen in a 10-mL sealed tube with microwave radiation for 2 h at 100° C. The reaction mixture was cooled to room temperature and the solid material was removed by filtration. The filtrate was concentrated under vacuum and the crude product (50 mg) was purified by preparative HPLC to give 2 mg (1%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-chloropyridin-2-yl)but-3-yn-2-ol as a light yellow solid: 1H NMR (400 MHz, DMSO) delta 8.61 (s, 1H), 8.38 (d, J=5.6 Hz, 1H), 8.16 (s, 1H), 7.98-7.82 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.26-7.24 (m, 1H), 7.06 (d, J=5.2 Hz, 3H), 6.44 (s, 1H), 5.06 (t, J=5.6 Hz, 1H), 4.61 (t, J=4.8 Hz, 2H), 3.83-3.80 (m, 2H), 1.82 (s, 3H); LC-MS: m/z=+451 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[CH:10][N:9]=1.[CH3:15][C:16]1[C:21]2[N:22]=[CH:23][NH:24][C:20]=2[CH:19]=[C:18]([OH:25])[CH:17]=1>CN(C=O)C>[Cl:14][C:12]1[N:11]=[CH:10][N:9]=[C:8]([O:25][C:18]2[CH:17]=[C:16]([CH3:15])[C:21]3[N:22]=[CH:23][NH:24][C:20]=3[CH:19]=2)[CH:13]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(O)cc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]cnc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
0.830 g (6.00 mmol) potassium carbonate were added to 307 mg (2.00 mmol) 4,6-dichloropyrimidine and 295 mg (2.00 mmol) 7-methyl-3H-benzimidazol-5-ol in 1.50 mL DMF and the mixture was stirred for 8 h at 50° C. Then the mixture was added to ice water added and extracted several times with EtOAc. The combined organic phases were dried on sodium sulphate, evaporated down and purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 1N aqueous sodium hydroxide solution and extracted with EtOAc. The organic phase was dried on sodium sulphate, filtered, evaporated down and dried under HV.
Reaction SMILES: [Cl:1][C:2]1[C:47]([Cl:48])=[CH:46][C:5]2[N:6]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C@@H:15]3[C@H:19]4[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@H:18]4[C@H:17]([N:25]4[C:29]5[N:30]=[CH:31][N:32]=[C:33]([NH:34][CH:35]6[CH2:37][CH2:36]6)[C:28]=5[CH:27]=[CH:26]4)[CH2:16]3)=[N:8][C:4]=2[CH:3]=1.CO.C=O.[BH3-][C:54]#N.[Na+]>C1COCC1>[Cl:1][C:2]1[C:47]([Cl:48])=[CH:46][C:5]2[N:6]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:44])[CH3:45])[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:14][C@@H:15]3[C@H:19]4[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@H:18]4[C@H:17]([N:25]4[C:29]5[N:30]=[CH:31][N:32]=[C:33]([NH:34][CH:35]6[CH2:36][CH2:37]6)[C:28]=5[CH:27]=[CH:26]4)[CH2:16]3)[CH3:54])=[N:8][C:4]=2[CH:3]=1
Reactant: CC1(C)O[C@@H]2[C@@H](CNCCCCc3nc4cc(Cl)c(Cl)cc4n3COCC[Si](C)(C)C)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCCCc1nc2cc(Cl)c(Cl)cc2n1COCC[Si](C)(C)C)C[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reaction time: 2 h

Procedure:
7-[(3aS,4R,6R,6aR)-6-({[4-(5,6-Dichloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)butyl]amino}methyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.222 g, 0.311 mmol) was dissolved in THF (5 ml) and MeOH (5 ml) and formaldehyde (0.05 ml, 0.621 mmol) was added at r.t. under N2. NaBH3CN (0.023 g, 0.373 mmol) was added at r.t. and the reaction left for 2 hrs. After this time LCMS analysis showed the reaction was complete so the reaction was quenched by addition of sat. NaHCO3 solution (10 ml), water (10 ml) and DCM (10 ml). The organic layer was separated and the aqueous layer was extracted with DCM (2×10 ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica flash column chromatography using between 100% DCM and 15% MeOH:95% DCM as eluent to give the product as a colorless oil
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]1([CH:19]=[CH:18][C:16]([OH:17])=CC=1)O.COCN[C:24](=[O:27])[CH:25]=[CH2:26]>CC(OCCOC)=O>[C:24]([O:17][CH2:16][CH2:18][CH2:19][CH3:12])(=[O:27])[CH:25]=[CH2:26]
Reactant: C=CC(=O)NCOC
Reactant: Oc1ccc(O)cc1
Agent: COCCOC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CC(=O)OCCCC

Procedure:
The polymer was dissolved in 250 g methyl glycol acetate and, after the addition of 800 mg p-toluene-sulfonic acid and 80 mg hydroquinone, mixed with 77 g N-methoxymethyl-acrylamide, sensitized as described in Example 1, and used for the production of a relief image.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:29][CH:30]([CH3:35])[C:31]([NH:33][NH2:34])=[O:32]>>[CH3:29][CH:30]([CH3:35])[C:31]([NH:33][NH:34][C:26]([CH:11]1[CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)[CH2:14][N:9]([C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH2:10]1)=[O:28])=[O:32]
Reactant: CC(C)C(=O)NN
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CC(C)C(=O)NNC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1

Procedure:
100 mg (0.25 mmol) of the compound from Example 44A and 51 mg (0.50 mmol) of 2-methylpropanehydrazide were reacted according to the General Method 11A. Yield: 80 mg (66% of theory)
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH:6]([C:9]#[C:10][CH2:11][CH2:12][CH3:13])[CH2:5][CH2:4]2)[O:2]1.N.[Na].S(=O)(=O)(O)O>O1CCCC1.O.CC(C)=O>[CH:9](/[CH:6]1[CH2:5][CH2:4][C:3](=[O:2])[CH2:8][CH2:7]1)=[CH:10]\[CH2:11][CH2:12][CH3:13]
Reactant: CCCC#CC1CCC2(CC1)OCCO2
Agent: N
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCC/C=C/C1CCC(=O)CC1
Reaction time: 8 h
Yield: 83.5 %

Procedure:
A solution of 4.5 g of 1,1-ethylenedioxy-4-(1-pentynyl)cyclohexane in 54 ml of tetrahydrofuran was treated dropwise with about 50 ml of pre-condensed ammonia in a sulphonation flask equipped with magnetic stirrer. The mixture was subsequently treated portionwise at -78° C. within 7 hours with 1.3 g of sodium. 1.5 hours after the last addition the ammonia was evaporated off and the reaction mixture was neutralized with 25% hydrochloric acid and left to stand overnight. Thereafter, the reaction mixture was partitioned three times in water/diethyl ether. The aqueous phases were back-extracted with diethyl ether. The organic phases were dried over magnesium sulphate and freed from solvent on a rotary evaporator. The pale yellow liquid obtained (3.8 g) was treated with 200 ml of acetone and 0.1 ml of concentrated sulphuric acid. The mixture was heated to reflux for 10 minutes, then treated with water and freed from acetone on a rotary evaporator. The residue was partitioned three times in methylene chloride/water. The aqueous phases were back-extracted with methylene chloride. The organic phases were dried over magnesium sulphate and evaporated. Chromatographic separation of the residual, yellow liquid (3.5 g) on silica gel with ethyl acetate/petroleum ether (vol. 7:93) gave 3.0 g (83.5%) of 4-(1E-pentenyl)cyclohexanone as a pale yellow liquid.
Reaction SMILES: [C:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[H][H]>[Ni].N>[CH2:17]([N:14]([CH2:15][CH3:16])[C:11]1[CH:12]=[CH:13][C:8]([C:3]2([CH2:1][NH2:2])[CH2:4][CH2:5][CH2:6][CH2:7]2)=[CH:9][CH:10]=1)[CH3:18]
Reactant: [H][H]
Reactant: CCN(CC)c1ccc(C2(C#N)CCCC2)cc1
Agent: [Ni]
Agent: N
Product: CCN(CC)c1ccc(C2(CN)CCCC2)cc1
Yield: 93.4 %

Procedure:
In a pressure reactor was placed 10.4 g (0.043 mole) of 1-cyano-1-(4-diethylaminophenyl)cyclopentane, 100 mL of methanolic ammonia, and 10 g of Ra-Ni catalyst. The reactor was charged with hydrogen and shaken at room temperature until the theoretical amount of hydrogen was taken up. The reaction mixture was filtered and the filtrate concentrated in vacuo to yield 9.9 g of the desired amine.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([CH:30]([F:32])[F:31])=[N:28][N:29]=2)[N:26]=1>>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH:30]([F:31])[F:32])=[N:28][N:29]=3)[N:26]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)c1nnc2ccc(Cl)nn12
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Product: FC(F)c1nnc2ccc(N3CCN(C(c4ccccc4)c4ccccc4)CC3)nn12

Procedure:
A mixture of 1-benzhydrylpiperazine and 6-chloro-3-difluoromethyl-1,2,4-triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 1 to give 6-(4-benzhydrylpiperazin-1-yl)-3-(difluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]([CH2:4][C:5](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])([OH:3])=[O:2].[C:16](OC(=O)C)(=O)C>>[CH3:16][O:2][C:1]([CH2:4][C:5](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])=[O:3]
Reactant: O=C(O)CC(=Cc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Product: COC(=O)CC(=Cc1ccccc1)C(=O)O

Procedure:
2-Carboxymethyl-3-phenylpropenoic acid (4.1 g.) and acetic anhydride (9 ml.) are heated in the steam bath for 70 minutes. The mixture is concentrated to dryness and the residue triturated with ether, yield 3.6 g. This anhydride is dissolved in 7 ml. of methanol and heated in the steam bath for 1 hour.
Reaction SMILES: C[O:2][C:3]1[C:12]([O:13]C)=[N:11][C:10]2[C:5](=[CH:6][C:7]([N+:25]([O-:27])=[O:26])=[CH:8][C:9]=2[CH2:15][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:17])[N:4]=1.[BrH:28]>C(O)(=O)C.C(OCC)C>[BrH:28].[O:2]=[C:3]1[C:12](=[O:13])[NH:11][C:10]2[C:5](=[CH:6][C:7]([N+:25]([O-:27])=[O:26])=[CH:8][C:9]=2[CH2:15][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:17])[NH:4]1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN(C)Cc3ccccc3)c2nc1OC
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CN(Cc1ccccc1)Cc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
213 mg (0.53 mmol) of N-(2,3-dimethoxy-7-nitro-quinoxalin-5-ylmethyl)-N-methylbenzylamine are dissolved in 4 ml of an approximately 25% solution of hydrogen bromide in acetic acid, and the solution is stirred at room temperature for 20 hours. The mixture is diluted with diethyl ether and then stirred for 10 minutes, and the solid is filtered off and washed with diethyl ether and a small amount of water. After drying under a high vacuum, the title compound is obtained in the form of a beige solid.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[O:27][CH3:28])=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:29][C:30]1[CH:31]=[C:32]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:33]=[CH:34][CH:35]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:15]([N:39]1[CH2:40][CH2:41][N:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH3:29])[CH:31]=3)[CH2:37][CH2:38]1)[N:16]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[O:27][CH3:28])[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)/C=C/c1cccc(F)c1N=C=Nc1cc(C(F)(F)F)ccc1OC
Reactant: Cc1cccc(N2CCNCC2)c1
Solvent: ClCCl
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(C)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
11.5 g (29.16 mmol) of methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]-imino}methylene)amino]phenyl}-2-propenoate (Example 18A), 5.14 g (29.16 mmol) of 1-(3-methylphenyl)piperazine and a spatula tip of silica gel are stirred in 300 ml of dichloromethane at room temperature for 1 hour and then under reflux for 20 hours. The product is obtained after chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10:1, 5:1).
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:16])([OH:15])[CH2:11][CH2:10]1)C1C=CC=CC=1>CCO.[Pd]>[NH2:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:16])([OH:15])[CH2:11][CH2:10]1
Reactant: CC1(O)CCC(NCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC1(O)CCC(N)CC1
Temperature: 25 °C
Reaction time: 31 h
Yield: 83 %

Procedure:
4-(Benzylamino)-1-methylcyclohexanol (335 mg, 1.53 mmol) was dissolved in EtOH (7.95 ml), followed by addition of Pd (10 wt % on activated carbon, 35 mg), and then the resulting liquid was stirred at room temperature under hydrogen stream for 31 hours. The resulting reaction liquid was filtered, concentrated under reduced pressure, and dried under vacuum, to obtain 164 mg of white solid (83%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:25])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH3:24])([CH2:21][CH2:22][OH:23])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([CH3:60])[CH:31]=[CH:30][C:29]([S:32]([O:35]CCC2(C)CCC3C(=C(C)C(C)=C(OCC4C=CC=CC=4)C=3C)O2)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[CH2:1]([O:8][C:9]1[C:10]([CH3:25])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH3:24])([CH2:21][CH2:22][OH:23])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:60][C:26]1[CH:31]=[CH:30][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC2(C)CCc3c(C)c(OCc4ccccc4)c(C)c(C)c3O2)cc1
Agent: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CCO)O2
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
Using the procedure of Example 8, rac.-6-benzyloxy-2,5,7,8-tetramethylchroman-2-ethanol was converted into rac.-6-benzyloxy-2,5,7,8-tetramethylchroman-2-ethanol p-toluenesulfonate which was obtained in essentially quantitative yield as a pale-pink glass.
Reaction SMILES: C([S:4][CH2:5][C:6]([N:8]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=O)C.N>>[SH:4][CH2:5][C:6]([N:8]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7]
Reactant: CO[C@@H]1C[C@@H](C(=O)O)N(C(=O)CSC(C)=O)C1
Agent: N
Product: CO[C@@H]1C[C@@H](C(=O)O)N(C(=O)CS)C1

Procedure:
Hydrolysis of trans-1-(2-acetylthio-1-oxoethyl)-4-methoxy-L-proline with an aqueous ammonia solution according to the procedure of Example 2 yields 1-(2-mercapto-1-oxoethyl)-trans-4-methoxy-L-proline.