Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[C:11]([CH:23]=[CH2:24])[C:12]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1>C(OCC)(=O)C.[Pd]>[CH2:23]([C:11]1[C:12]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[N:8][N:7]2[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH3:24]
Reactant: C=Cc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Reaction time: 6 h
Yield: 103.8 %

Procedure:
To a solution of 1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-4-vinyl-1H-indazole (1.35 g, 4.11 mmol) in ethyl acetate (40 ml) was added 10%-palladium/carbon (containing 50% water, 50 mg), and the resulting mixture was stirred for 6 hours at ordinary temperature and atmospheric pressure under a hydrogen atmosphere. To the mixture was further added 10%-palladium/carbon (containing 50% water, 670 mg), and stirred for another 1.5 hours. The reaction mixture was filtered by the use of Celite and washed with methanol, and then the filtrate was concentrated under reduced pressure to obtain 4-ethyl-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole (1.41 g).
Reaction SMILES: COC[C@@H]1[C@H](C=O)[C@]1(C)C1C=C(C(C)C)C=C(C(C)C)C=1.CC12C(C)(C)[C:26]([C:32]([O:34][CH2:35][C@@H:36]3[C@@H:38]([CH2:39][O:40]CC)[C@:37]3([CH3:55])[C:43]3[CH:48]=[C:47]([CH:49]([CH3:51])[CH3:50])[CH:46]=[C:45]([CH:52]([CH3:54])[CH3:53])[CH:44]=3)=O)(CC1)OC2=O>>[CH2:32]([O:34][CH2:35][C@@H:36]1[C@@H:38]([CH:39]=[O:40])[C@@:37]1([CH3:55])[C:43]1[CH:44]=[C:45]([CH:52]([CH3:53])[CH3:54])[CH:46]=[C:47]([CH:49]([CH3:51])[CH3:50])[CH:48]=1)[CH3:26]
Reactant: CCOC[C@@H]1[C@@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Agent: COC[C@@H]1[C@H](C=O)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Product: CCOC[C@@H]1[C@@H](C=O)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 98 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 45 but using Intermediate 44b as the starting material afforded the title compound (39 mg, 98% yield) as a colorless oil:
Reaction SMILES: [OH-:1].[Na+].O.Cl[CH2:5][CH:6]([OH:9])[CH2:7]Cl.[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl>>[CH2:5]([O:1][CH2:10][CH:12]1[O:14][CH2:13]1)[CH:6]1[O:9][CH2:7]1.[CH2:5]1[O:9][CH:6]1[CH2:7][OH:14]
Reactant: [OH-]
Reactant: ClCC1CO1
Reactant: OC(CCl)CCl
Agent: [Na+]
Solvent: O
Product: C(OCC1CO1)C1CO1
Product: OCC1CO1

Procedure:
Into a 500 ml 3-neck flask was weighed 22.8 grams (0.100 mole) of para bisphenol A, 8.0 grams (0.200 mole) of sodium hydroxide and 208 grams (11.56 moles) of water. The mixture was agitated under a nitrogen purge until complete solution had occurred. Into this mixture was charged a solution of varying amounts of 1,3-di-chloro-2-propanol in 185 grams (2 moles) of epichlorohydrin. The mixture was then agitated for exactly one hour (3600 s) at a controlled temperature of 30° C. After this time, samples were withdrawn for analysis. The amount of bisphenol A which had been converted (phenolic OH conversion) was determined by ultraviolet spectrophotometer. The amount of diglycidyl ether and glycidol which had been formed in the reaction was determined by gas chromatography analysis. The amount of glycerine which had been formed in the reaction was determined by liquid chromatography analysis. The yield of product based on the amount of epichlorohydrin converted was determined from the phenolic OH conversion and the amounts of the above by-products which were formed from the epichlorohydrin. Ths is reported as the % yield based on epichlorohydrin. The results of these experiments are shown in the following Table.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH2:9]([OH:14])[CH:10]=[CH:11][C:12]#[CH:13]>C(NC(C)C)(C)C.[Cu]I.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>[OH:14][CH2:9]/[CH:10]=[CH:11]/[C:12]#[C:13][C:4]1[CH:3]=[C:2]([C:13]#[C:12]/[CH:11]=[CH:10]/[CH2:9][OH:14])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CC=CCO
Reactant: Ic1cccc(I)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: OC/C=C/C#Cc1cccc(C#C/C=C/CO)c1
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of 1,3-diiodobenzene (2.64 g, 8.0 mmol) in diisopropylamine (25 mL) under a nitrogen atmosphere were added copper(I) iodide (75 mg, 0.4 mmol) and tetrakis(triphenylphosphine)palladium (80 mg, 0.07 mmol). After the mixture stirred for 1 h, a solution of 2-penten-4-yn-1-ol (2.0 g, 24.0 mmol) in diisopropylamine (10 mL) was added. After stirring at 60° C. for 16 h, the reaction mixture was filtered and the filtrate evaporated to dryness. The product was purified by flash chromatography using toluene/ethyl acetate (9:1) graduated to ethyl acetate as eluent to give 1.35 g (71%) of (E)(E) 5-[3-(5-hydroxy-pent-3-en-1-ynyl)-phenyl]-pent-2-en-4-yn-1-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]1[CH:18]=[C:17]([N+:19]([O-])=O)[N:16]=[CH:15]1.[NH4+:22].[Cl-]>CCO.O.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]1[CH:18]=[C:17]([NH2:19])[N:16]=[CH:15]1.[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]1[C:18]([NH2:22])=[CH:17][N:16]=[CH:15]1
Reactant: [NH4+]
Reactant: COc1ccc2[nH]cc(CCn3cnc([N+](=O)[O-])c3)c2c1
Agent: [Fe]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COc1ccc2[nH]cc(CCn3cnc(N)c3)c2c1
Product: COc1ccc2[nH]cc(CCn3cncc3N)c2c1
Temperature: 85 °C

Procedure:
To a solution of 5-methoxy-3-(2-(4-nitro-1H-imidazol-1-yl)ethyl)-1H-indole in EtOH/H2O (1.8 mL/0.9 mL), NH4Cl (158 mg, 2.95 mmol) and Fe (99 mg, 1.77 mmol) was added. The resulting black mixture was heated to 85° C. for 30 min, then it was filtered while hot and the filter cake was rinsed with EtOH. The filtrate was concentrated in vacuo and the residue partitioned between DCM and aq. 1 N NaOH-solution. The org. layer was separated and the aq. layer wa extracted with DCM. The combined organic extracts were washed with brine, dried (MgSO4), filtered and the solvents were removed under reduced pressure to yield the title compound in mixture with 1-(2-(5-methoxy-1H-indol-3-yl)ethyl)-1H-imidazol-5-amine as a dark brown solid, which was used in the next step without further purification. LC-MS conditions A: tR=0.52 min, [M+H]+=257.22.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[OH:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[N:1]([N:9]1[CH2:10][CH2:11][CH:6]([OH:5])[CH2:7][CH2:8]1)=[O:3]
Reactant: O=N[O-]
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CCC(O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add a solution of sodium nitrite (13.8 g, 200 mmol) in water (40 mL) to 4-hydroxy piperidine (10.1 g, 100 mmol) in water (20 mL). Cool the mixture to 0° C. on an ice bath. Add acetic acid (8.6 mL, 150 mmol) dropwise over 20 minutes. After the addition, continue stirring at 0° C. for 30 minutes, slowly warm up to room temperature and stir at room temp for 5 hours. Add sodium carbonate (15.9 g, 150 mmol) in portion to quench the acid. Extract the reaction with ethyl acetate (3×60 mL), combine the organic, dry over sodium sulfate, filter and concentrate to afford the desired product as yellow oil. Yield: 12.9 g, (98%).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([O-])([O-])=O.[K+].[K+].OC1C=CC(C=O)=CC=1.[Br:37]CCCCCCCCCCBr>>[Br:37][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:11][C:12]1[CH:21]=[CH:20][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: BrCCCCCCCCCCBr
Reactant: CCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: O=C([O-])[O-]
Agent: O=Cc1ccc(O)cc1
Agent: [K+]
Product: O=Cc1ccc(OCCCCCCCCCCBr)cc1

Procedure:
Synthesized as described above for compound 1. Quantities: K2CO3 (4.75 g, 34 mmol), p-hydroxybenzaldehyde (3.57 g, 29 mmol), 1,10-dibromodecane (8.6 mL, 38 mmol). Yield 10.0 g (quant.). 1H NMR: δH (CDCl3; 300 MHz): 1.22-1.52 (12 H, m, CH2), 1.80 (4 H, m, O—CH2—CH2/Br—CH2—CH2), 3.36 (2 H, t, 3J=6.9 Hz, Br—CH2), 4.00 (2 H, t, 3J=6.5 Hz, O—CH2), 6.95 (2 H, d, 3J=8.7 Hz, Ar—H), 7.79 (2 H, d, 3J =8.8 Hz, Ar—H), 9.84 (1 H, s, COH). 13C NMR: δC (CDCl3; 75 MHz): 25.9, 28.1, 28.7, 29.0, 29.3, 29.4, 29.5, 32.8, 34.0, 68.4, 114.7, 129.7, 131.9, 164.2, 190.7.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][CH:52]=[C:53]([C:58]#[N:59])[CH:54]=4)[O:49][C:48]=3[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][CH:52]=[C:53]([C:58]#[N:59])[CH:54]=4)[O:49][C:48]=3[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(C#N)cc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: N#Cc1ccc2oc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)c(=O)c2c1
Yield: 94 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(6-cyano-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a yellow solid (33 mg, 94%). 1H NMR (400 MHz, DMSO-d6): δ 8.51 (d, J=2 Hz, 1H), 8.27 (dd, J=2 and 8 Hz, 1H), 7.95 (d, J=8 Hz, 1H), 7.46-7.33 (m, 7H), 7.18-7.14 (m, 2H), 2.44-2.36 (m, 2H), 2.20-2.12 (m, 2H), 2.07-1.97 (m, 1H), 1.73-1.63 (m, 1H). LCMS (Method F): RT=8.47 min, [M+H]+=393.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[S:27](Cl)(=[O:29])=[O:28]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:11]([S:10][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=1[NH:1][S:27]([C:19]1[O:18][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=1)(=[O:28])=[O:29])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: N#Cc1ccc(N)c(SCc2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: N#Cc1ccc(NS(=O)(=O)c2cc3ccccc3o2)c(SCc2ccccc2)c1
Yield: 99.4 %

Procedure:
Following General Procedure B, the title compound (752 mg, 47%) was prepared from 4-amino-3-(benzylthio)benzonitrile (430 mg, 1.80 mmol), benzofuran-2-sulfonyl chloride (391 mg, 1.80 mmol), and DMAP (cat.) in pyridine (3 ml).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][O:11][CH2:12][CH2:13][CH2:14][C:15](OC)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]([CH2:14][CH2:13][CH2:12][O:11][CH3:10])=[N:9][N:8]=2)[CH:7]=1
Reactant: COCCCC(=O)OC
Reactant: NNc1ccc(Br)cn1
Product: COCCCc1nnc2ccc(Br)cn12

Procedure:
A mixture of 18.80 g of (5-bromopyridin-2-yl)hydrazine [77992-44-0] and 14.54 g of methyl 4-methoxybutyrate [29006-01-7] is heated to reflux over 16 hours. The reaction solution is subsequently cooled and purified by means of flash chromatography (SiO2 60F). The title compound is identified on the basis of the Rf value.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[C:5]2=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[F:17][C:13]1[CH:12]=[C:11]([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:35][CH:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]4)=[N:3][CH:4]=3)[NH:8][N:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: Fc1cccc(-c2n[nH]c3nc(Cl)ncc23)c1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2ncc3c(-c4cccc(F)c4)n[nH]c3n2)CC1
Yield: 6 %

Procedure:
The compound was prepared from 6-chloro-3-(3-fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 9) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoro-acetic acid in an analogous manner as described in Example 4 and was purified by HPLC (Gilson) to give a free base (6% yield). MS (M+H)+, 391.25.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:32]3[CH:31]=[C:30]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:24][CH:25]=4)[CH:35]=[CH:34][CH:33]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Brc1cccc(-c2ccccc2)c1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3cccc(-c4ccccc4)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 3-bromobiphenyl.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][OH:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](N1C=CN=C1)([N:22]1C=CN=C1)=[O:21].N.O>C1COCC1>[C:20]([O:19][CH2:18][C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])(=[O:21])[NH2:22]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1F
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](COC(N)=O)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
In a 250 mL flask equipped with magnetic stirrer, N-(t-butyloxycarbonyl)-o-fluorophenylalaninol (0.096 mole, 2.15 g) was dissolved in 200 ml of THF and was added with 1,1'-carbonyldiimidazole (0.010 mol, 1.62 g) at 0° C. The reaction mixture was stirred at room temperature for 2 hours, followed by the injection of ammonia at 0° C. for 30 min. Following elevating to room temperature, water was added to terminate the reaction. The organic layer was extracted 3 times with dichloromethane, dried over magnesium sulfate and distilled in vacuo, to give a solid. This was recrystalized in a solution mixture of n-hexane and diethyl ether, to produce 1.93 g of O-carbamoyl-N-(t-butyloxycarbonyl)-o-fluorophenylalaninol: Yield 75%.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH2:9][OH:10])[C:3]=1[CH3:11].[CH3:12][O-:13].[Na+]>CN(C)C=O.CO>[OH:10][CH2:9][C:4]1[C:3]([CH3:11])=[C:2]([O:13][CH3:12])[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: Cc1cnc(CO)c(C)c1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1c(C)cnc(CO)c1C
Yield: 55 %

Procedure:
In a round bottom flask equipped with a stirrer, a condenser and a nitrogen bubbler, 4-Chloro-2-hydroxymethyl-3,5-Lutidine (1 eq.) was dissolved in Dimethylformamide (3-9 volumes) and Methanol (1.5-4.5 volumes). Sodium methoxide (4 eq.) was added and the temperature was raised to (95-100ℑ C.). At the end of the reaction the solvent was distilled under vacuum. Water (2 volumes) was added to the residue and the product was extracted with dichloromethane (2×4 volumes). The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product, 2-hydroxymethyl-4-Methoxy-3,5-lutidine, was obtained in 55% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[S:7])=[CH:4][CH:3]=1.[CH:12]([C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18]([NH2:20])=[O:19])=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[S:7][CH:12]([C:14]3[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=3[O:16][CH2:17][C:18]([NH2:20])=[O:19])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NNC(=S)c1ccc(Cl)cc1
Reactant: NC(=O)COc1ccccc1C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)COc1ccccc1C1NN=C(c2ccc(Cl)cc2)S1
Reaction time: 0.17 h

Procedure:
To a heterogeneous mixture of 4-chloro-thiobenzoic acid hydrazide (1.3 mmol) in 12 mL of CH2Cl2 is added 2-(2-formylphenoxy)acetamide (1.53 mmol) and DIEA (1.53 mmol). After 10 minutes the mixture become homogenous and the reaction is complete by TLC and LCMS to give 2-(2-(5-(4-chlorophenyl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)phenoxy)-acetamide which is used as such in the next step without evaporation of the solvent.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][OH:10])[CH2:4][CH2:3]1.N1([O:20][C:21](=O)[C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[C:24]([O:29][CH3:30])[CH:23]=2)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)CC)C>ClCCl>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][OH:10])[CH2:4][CH2:3]2)=[O:20])=[CH:23][C:24]=1[O:29][CH3:30]
Reactant: COc1cc(C(=O)On2nnc3ccccc32)ccc1N
Reactant: NC1CCN(CCO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(CCO)CC2)ccc1N
Reaction time: 8 h
Yield: 36.9 %

Procedure:
To a mixture of 0.70 g (3.23 mmole) of 2-(4-amino-piperidin-1-yl)-ethanol, 0.92 g of 4-amino-3-methoxy-benzoic acid benzotriazol-1-yl ester, and 5 mL of dimethylformamide was added 1.63 g (16.1 mmole) of triethylamine. The mixture was stirred overnight, then taken up in 150 mL of dichloromethane and washed twice with saturated aqueous sodium bicarbonate, once with water, once with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-80:20) to give 0.35 g of 4-amino-N-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-3-methoxy-benzamide.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:9][C:10]1([O:21][CH2:22][CH3:23])[CH2:15][NH:14][CH:13]([C:16](OCC)=[O:17])[CH2:12][CH2:11]1)[CH3:8]>C1COCC1>[CH2:22]([O:21][C:10]1([O:9][CH2:7][CH3:8])[CH2:15][NH:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)[CH3:23]
Reactant: CCOC(=O)C1CCC(OCC)(OCC)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC1(OCC)CCC(CO)NC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A suspension of LAH (0.47 g, 12.25 mmol) in anhydrous THF (5 mL) was added a solution of ethyl 5,5-diethoxypiperidine-2-carboxylate (0.6 g, 2.45 mmol) in anhydrous THF (5 mL) dropwise at rt. The resulting mixture was refluxed at 70° C. for overnight. The reaction mixture was cooled down to 0° C. and quenched sequentially with water (0.47 g), 15% NaOH (0.47 g) and water (1.41 g). The resulting suspension was stirred at rt for 1 h and filtered. The filtrate was concentrated in vacuo to give desired rac-(5,5-diethoxypiperidin-2-yl)methanol in 95% yield as colorless oil. 1H NMR (CDCl3, 400 MHz) δ 3.54-3.32 (m, 6H), 3.11-3.04 (m, 1H), 2.56-2.46 (m, 2H), 2.05-2.00 (m, 1H), 1.52-1.23 (m, 3H), 1.15-1.07 (m, 6H).
Reaction SMILES: [C:1]1([CH3:42])[CH:6]=[CH:5][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][CH2:30][O:31][C:32]4[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=4[C:34]([O:36]C)=[O:35])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[C:1]1([CH3:42])[CH:2]=[CH:3][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][CH2:30][O:31][C:32]4[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=4[C:34]([OH:36])=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccccc1OCCC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cc3)CC2)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCOc4ccccc4C(=O)O)CCCCC3)CC2)cc1
Reaction time: 18 h
Yield: 79.8 %

Procedure:
To a solution of methyl 2-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethoxy]benzoate (synthesized in Example 39) (221 mg) in methanol (5 mL) was added a sodium hydroxide (77 mg) solution in water (3 mL) dropwise at room temperature. The solution was stirred for 18 hours. After neutralizing the reaction solution with 2N hydrochloric acid, silica gel was added to the solution. The solution was concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, chloroform-methanol (10:1)] to give the title compound (172 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1O[C:7]([CH3:9])=[CH:6][C:5](=[O:10])[C:4]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[OH:1][CH2:2][C:3]1[N:22]([OH:23])[C:7]([CH3:9])=[CH:6][C:5](=[O:10])[C:4]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: COc1ccc(COc2c(CO)oc(C)cc2=O)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(COc2c(CO)n(O)c(C)cc2=O)cc1
Reaction time: 7 h
Yield: 8.3 %

Procedure:
To a solution of 4 g of 6-hydroxymethyl-5-p-methoxybenzyloxy-2-methyl-4-pyrone in 50 ml of pyridine was added 5 g of hydroxylamine hydrochloride at room temperature. The mixture was stirred at 70° to 75° C. for 7 hours. After the reaction liquid was concentrated under reduced pressure, the residue was dissolved in 200 ml of chloroform and washed in succession with water, 5% cold hydrochloric acid and saturated aqueous sodium hydrogencarbonate solution. After drying over anhydrous magnesium sulfate, the chloroform layer was dried and concentrated under reduced pressure. The concentrate was separated and purified by flash column chromatography (eluting solution; chloroform: methanol=20:1) using Wako Gel C-300 (100 g) to give 350 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:11])[CH:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])[CH2:21][CH2:22]2)=[O:8])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3Cl)CC2)c(C)c1
Yield: 105 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-2-chlorobenzoic acid (5 g) and 1-(2,4-dimethylphenyl)piperazine (4 g), the title compound (9 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14](=[S:18])[NH:13][C:12]=2[CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[C:21](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14]([S:18][CH3:21])=[N:13][C:12]=2[CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)NC(=S)CCC2
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSC1=Nc2cc(NC(=O)OC(C)(C)C)ccc2CCC1
Reaction time: 12 h
Yield: 42.1 %

Procedure:
A solution of (2-thioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-yl)-carbamic acid tert-butyl ester (5.0 g, 17.1 mmol) and potassium carbonate (4.7 g, 34.0 mmol) in acetone (400 mL) was treated with iodomethane (2.5 mL, 5.7 g, 40.0 mmol). The mixture was stirred for 12 h and concentrated. The residue was partitioned between water (100 mL) and DCM (200 mL). The aqueous phase was extracted again with DCM and the combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography with DCM/MeOH (9:1) to give (2-methylsulfanyl-4,5-dihydro-3H-benzo[b]azepin-8-yl)-carbamic acid tert-butyl ester (2.2 g, 7.2 mmol, 42%): 1H NMR (300 MHz, CDCl3) δ 7.1 (m, 3H), 2.92 (t, 1H), 2.81 (t, 1H), 2.55 (s, 3H), 2.4 (q, 2H), 2.32 (q, 2H), 1.6 (s, 9H); MS (m/e) 307 (M+1).