Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]=2[CH:4]=[CH:3]1>[Pd].CCO>[CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]=2[CH:4]=[CH:3]1
Reactant: CCOC(=O)C=C1CCCc2c1ccn2C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CCCc2c1ccn2C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
Pd—C (1.3 g, 5%) is added to a solution of a mixture of E/Z isomers of ethyl 2-(1-methyl-6,7-dihydro-1H-indol-4(5H)-ylidene)acetate (3.4 g, 15.50 mmoles) in 100 mL de EtOH, and the resulting solution is stirred under hydrogen atmosphere (25 psi) in a Parr hydrogenator for 8 hours. The reaction mixture is purged with nitrogen, filtered through Celite and the solvent is evaporated under reduced pressure to obtain ethyl 2-(1-methyl-4,5,6,7-tetrahydro-1H-indol-4-yl)acetate (3.4 g, 15.36 mmol, 99%, oil).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[N:16][N:17]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:18]=3[CH:19]=[CH:20][CH:21]=2)=[O:12])[CH:6]=[CH:5][N:4]=1.Cl.[NH+]1C=CC=CC=1>C(OCC)(=O)C.O>[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[N:16][N:17]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:18]=3[CH:19]=[CH:20][CH:21]=2)=[O:12])[CH:6]=[CH:5][NH:4]1
Reactant: COc1cc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)ccn1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCc1cc[nH]c(=O)c1)c1cccc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide (38 mg, 0.10 mmol) and pyridinium hydrochloride (117 mg, 1.01 mmol) were heated to 125° C. in a sealed tube. After 10 minutes, the mixture was cooled to room temperature and diluted with ethyl acetate (3 mL) and water (3 mL). The organic layer was washed with water (3×3 mL) and concentrated at 45° C. under a stream of nitrogen. The residue was dissolved in CH2Cl2 (3 mL) and concentrated (repeated 3 times). The solid was triturated with ether (3 mL), filtered and air dried to afford the title compound as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.Cl.[NH2:18][OH:19].C(N(CC)CC)C>C(O)C>[OH:19][N:18]=[C:13]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:16][CH:15]=1)[NH2:14]
Reactant: NO
Reactant: N#Cc1ccc(COC2CCOCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NO)c1ccc(COC2CCOCC2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-[(tetrahydro-2H-pyran-4-yloxy)methyl]benzonitrile (Step 1, 780 mg, 3.59 mmol), hydroxylamine hydrochloride (549 mg, 7.90 mmol) and triethylamine (1.10 mL, 7.90 mmol) in ethanol (20 mL) was stirred and heated at reflux for 1 h. After being cooled to rt, the reaction mixture was evaporated to dryness. The resulting material was treated with ethyl acetate, and the solid was filtered off. The ethyl acetate solution was washed with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was stirred in hexane and filtered. After evaporation of the solvent, the title compound was obtained (857 mg, 95%): 1H NMR (400 MHz, CDCl3) δ 7.55 (d, 2H), 7.40 (d, 2H), 4.81 (s, 2H), 4.06-3.99 (dd, 2H), 3.81 (d, 2H), 3.48-3.40 (m, 2H), 2.15-2.02 (m, 1H), 1.78-1.72 (dd, 2H), 1.52-1.40 (m, 2H); ES-MS m/z 251, HPLC RT (Method E) 0.56 min.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]#N)[CH:41]=1)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].C([Al+]CC(C)C)C(C)C.C[OH:59].[H-]>C1C=CC=CC=1.O>[CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=[O:59])[CH:41]=1)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCC(COCc1cccc(C#N)c1)OCCCCCCCCCCCCCCCC
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(C=O)c1)OCCCCCCCCCCCCCCCC
Yield: 40 %

Procedure:
A solution of 1,2-di-O-(n-hexadecyl)-3-O-(3-cyanobenzyl)-glycerol (5.0 g., 7.6 mmoles) and diisobutylaluminum hydride (1.17 g., 8.2 mmoles) in benzene (25 ml.) was stirred for 16 hours at ambient temperature. The reaction mixture was treated with methanol (4.22 ml.) and water (2.5 ml.) and stirred to decompose unreacted hydride, and then filtered and extracted with benzene (3×25 ml.). The combined benzene extract was dried (Na2SO4), filtered and evaporated in vacuo to an oil, which was purified by silica gel chromatography (elution with benzene) [2.0 g., 40% yield, oil, ir (CHCl3) 1700 cm-1, n.m.r. (CDCl3) δ10.1 (s, 1, --ArCHO)].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[O:18]1[C:22]2[CH:23]=[CH:24][C:25](B(O)O)=[CH:26][C:21]=2[CH:20]=[CH:19]1>>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:2]3[CH:3]=[C:4]4[N:10]([O:11][C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH:9]=[CH:8][C:5]4=[N:6][CH:7]=3)=[CH:26][C:21]=2[CH:20]=[CH:19]1
Reactant: Brc1cnc2ccn(Oc3ccccc3)c2c1
Reactant: OB(O)c1ccc2occc2c1
Product: c1ccc(On2ccc3ncc(-c4ccc5occc5c4)cc32)cc1
Yield: 25 %

Procedure:
The entitled compound was prepared from 6-bromo-1-phenoxy-1H-pyrrolo[3,2-b]pyridine and 1-benzofuran-5-ylboronic acid in a 25% yield according to the procedure described in example 23.
Reaction SMILES: ClC1N=C(C)N([CH2:8][C:9]2[S:24][C:12]3[N:13]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:14](=[O:19])[N:15]([CH3:18])[C:16](=[O:17])[C:11]=3[C:10]=2[C:25]([N:27]2[CH2:31][C@H:30]([OH:32])[CH2:29][O:28]2)=[O:26])C=1Cl.[N:34]1[CH:35]=[CH:36][N:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=12.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[OH:32][C@@H:30]1[CH2:29][O:28][N:27]([C:25]([C:10]2[C:11]3[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[N:13]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:12]=3[S:24][C:9]=2[CH2:8][C:36]2[N:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]3=[N:34][CH:35]=2)=[O:26])[CH2:31]1
Reactant: c1ccn2ccnc2c1
Reactant: Cc1nc(Cl)c(Cl)n1Cc1sc2c(c1C(=O)N1C[C@H](O)CO1)c(=O)n(C)c(=O)n2CC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)N3C[C@H](O)CO3)c(Cc3cnc4ccccn34)sc21

Procedure:
The product of example 3 part b (1 g), imidazolo[1,2-a]pyridine (0.4 ml), potassium carbonate (0.35 g) and THF (20 ml) were stirred under nitrogen for 1 h. Warer was added to the reaction and extracted with ethyl acetate (×2). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (SiO2/9:1 ethyl acetate-hexane and the ethyl acetate) to give the sub-title compound as a colourless oil. LCMS(ESI) 4275 [M+H]+
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)[CH3:2].[F:15][C:16]([F:30])([F:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](O)=[O:27].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:15][C:16]([F:29])([F:30])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([N:12]1[CH2:11][CH2:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[CH2:14][CH2:13]1)=[O:27]
Reactant: O=C(O)Cc1ccccc1OCC(F)(F)F
Reactant: CCc1cccc(N2CCNCC2)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCc1cccc(N2CCN(C(=O)Cc3ccccc3OCC(F)(F)F)CC2)c1
Reaction time: 48 h

Procedure:
1-(3-ethylphenyl)piperazine from the previous step was dissolved in 1 mL dry DMF, and to the solution was added 0.03 g (0.128 mmol) 2-(2,2,2-trifluoroethoxy)phenylacetic acid, 0.017 g (0.128 mmol) HOBT, and 0.024 g (0.128 mmol) EDC. The reaction was stirred for 2 days, after which time the solvent was removed in vacuo and the resulting residue partitioned between EtOAc/H2O. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with H2O, brine, dried over Na2SO4 and filtered. Removal of the solvent and subsequent purification via preparative TLC (2:1 Hexane/EtOAc) yielded the title compound as the free base. This was dissolved in 20 mL EtOAc and an excess of ethanolic HCl was added. The solvent was removed to give the Hcl salt of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(NCC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([OH:53])(=[O:52])[CH2:46][CH2:47][CH2:48][CH2:49][C:50]#[CH:51]>CN(C=O)C.[Cu]I>[C:18]([C:14]1[C:13](=[O:20])[NH:12][C:11]2[S:10][CH:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:51]#[C:50][CH2:49][CH2:48][CH2:47][CH2:46][C:45]([OH:53])=[O:52])[CH:7]=[CH:6][CH:5]=3)[C:16]=2[C:15]=1[OH:17])#[N:19]
Reactant: C#CCCCCC(=O)O
Reactant: N#Cc1c(O)c2c(-c3cccc(Br)c3)csc2[nH]c1=O
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: N#Cc1c(O)c2c(-c3cccc(C#CCCCCC(=O)O)c3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(3-bromo-phenyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (50 mg, 0.15 mmol) in 1.5 mL DMF was added diethylamine (0.16 mL, 1.5 mmol), followed by copper(I) iodide (trace), Pd(PPh3)Cl2 (3.5 mg, 0.005 mmol), and triphenylphosphine (12 mg, 0.04 mmol). The resulting mixture was stirred at rt for 5 min, after which hept-6-ynoic acid (63 μL, 0.5 mmol) was added. The reaction was then heated to 120° C. using microwave reactor for 25 min, filtered, concentrated and purified by reverse phase HPLC to give the titled compound. MS (ESI) m/e 391 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.54 (m, 4H), 2.22 (m, 4H), 6.68 (s, 1H), 7.21–7.26 (m, 2H), 7.37–7.44 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2

Procedure:
Prepared from methyl 5-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-5-(3-pyridyl)pent-4-enoate by hydrolysis with sodium hydroxide solution.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)[CH3:2].[Cl:11][S:12](O)(=[O:14])=[O:13]>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[S:12]([Cl:11])(=[O:14])=[O:13])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCOc1ccc(C)cc1
Solvent: ClCCl
Product: CCOc1ccc(C)cc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
A solution of 6.8 g (50 mmol) of 4-ethoxy-toluene in 20 mL of dichloromethane was added to a solution of 10 mL (150 mmol) of chlorosulfonic acid in 10 mL of dichloromethane at 0° C. with cooling and stirring. The mixture was stirred 1 hour at 0° C. and was then warmed to ambient temperature and stirred another hour. The resulting tan solution was poured into 200 mL of ice water and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated by evaporation under reduced pressure. The residual 7.9 g (68 percent of theory) of light tan solid melting at 59°-61° C. was the title compound.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26](O)=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1>>[CH:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:16])[N:2]([NH:1][C:26](=[O:27])[CH2:25][C:20]3[CH:19]=[C:18]([F:17])[CH:23]=[C:22]([F:24])[CH:21]=3)[N:11]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: Nn1nc(C2CCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(C2CCC2)c2ccccc2c1=O

Procedure:
The product of Example 67A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.35-8.28 (m, 1H), 8.01-7.94 (m, 1H), 7.94-7.85 (m, 2H), 7.20-7.10 (m, 3H), 4.12-3.99 (m, 1H), 3.76 (s, 2H), 2.42-2.22 (m, 4H), 2.14-2.00 (m, 1H), 1.89-1.76 (m, 1H); MS (ESI) m/z 370 (M+H)+.
Reaction SMILES: [C:1]([C:5]1([OH:20])[C:9]([CH3:11])([CH3:10])[CH2:8][O:7][CH:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.C1C(=O)N([Br:33])C(=O)C1.[Cl-].[Na+]>O>[Br:33][C:15]1[CH:16]=[CH:17][C:12]([CH:6]2[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([OH:20])[C:9]([CH3:11])([CH3:10])[CH2:8][O:7]2)=[CH:13][C:14]=1[O:18][CH3:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C2OCC(C)(C)C2(O)C(C)(C)C)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C2OCC(C)(C)C2(O)C(C)(C)C)ccc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
2.16 g (7.77 mmol) of 3-t-butyl-3-hydroxy-2-(3-methoxyphenyl)-4,4-dimethyl-2,3,4,5-tetrahydrofuran (compound (5)) was added to a mixed solvent of 20 ml of THF and 2 ml of H2O, followed by stirring at 0° C. To this solution, 1.54 g (8.65 mmol) of NBS was added, and while gradually raising the temperature to room temperature, stirring was continued overnight. Then, 140 mg (0.787 mmol) of NBS was further added, followed by stirring for 6 hours. The reaction mixture was put into a saturated sodium chloride aqueous solution and extracted with ethyl acetate. The extract layer was washed sequentially with an aqueous sodium thiosulfate solution and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated. The concentrated product was crystallized from a mixed solvent of ethyl acetate and hexane to obtain 1.323 g of 2-(4-bromo-3-methoxyphenyl)-3-t-butyl-3-hydroxy-4,4-dimethyl-2,3,4,5-tetrahydrofuran (compound (6)) in a yield of 47.7%.
Reaction SMILES: [O:1]([CH2:13][CH:14]=[CH2:15])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:16]1([C:22](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[C:22]([O:12][CH2:11][C@H:9]1[O:10][C@H:2]([O:1][CH2:13][CH:14]=[CH2:15])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C=CCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: C=CCO[C@H]1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A solution of allyl α-D-glucopyranoside (1) (prepared according to R. E. Wing, J. N. BeMiller, Carbohydr. Res. 1969, 10, 441) (12.5 g, 56.8 mmol) and triphenylmethyl chloride (20.0 g, 71.7 mmol) in dry pyridine (120 ml) was stirred at r.t. for 12 h, and at 60° for 1 h. After the addition of triphenylmethyl chloride (12.0 g, 43.0 mmol), the solution was stirred at 60° until all starting material has disappeared (3-4 h). H2O (120 ml) was added to the still warm solution. Extraction with EtOAc, extraction of the combined org. layers with 1M aq. H2SO4 and brine, evaporation of the organic layer and FC (400 g SiO2, toluene/actone 2:1→toluene/acetone 1:1) gave 23.3 g (90%) of 2. Grey glassy solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1[C:29]([CH:35]=O)=[N:30][CH:31]=[C:32]([CH3:34])[CH:33]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:35][C:29]1[C:28]([CH3:27])=[CH:33][C:32]([CH3:34])=[CH:31][N:30]=1)[CH2:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CC(C)(C)OC(=O)NCCCCNCc1ncccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cnc(CN(CCCCNC(=O)OC(C)(C)C)Cc2ncccc2-c2ccccc2)c(C)c1

Procedure:
Using General Procedure B, reaction of {4-[(3-Phenyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester, 3,5-Dimethyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave {4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-(3-phenyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3) δ 1.03-1.21 (m, 4H), 1.44 (s, 9H), 1.89 (s, 3H), 2.24 (s, 3H), 2.29-2.40 (m, 2H), 2.76-2.90 (m, 2H), 3.63 (s, 2H), 3.79 (s, 2H), 4.85 (s, 1H), 7.09 (s, 1H), 7.26 (dd, 1H, J=7.6, 4.5 Hz), 7.54 (dd, 1H, J=7.8, 1.8 Hz), 8.08 (s, 1H), 8.60 (dd, 1H, J=4.7, 1.2 Hz). Conversion to the HBr salt gave COMPOUND 233 as a white solid (40.3 mg, 88%). 1H NMR (D2O) δ 1.36-1.52 (m, 4H), 2.33 (s, 3H), 2.46 (s, 3H), 2.58-2.69 (m, 2H), 2.79-2.91 (m, 2H), 4.09 (s, 2H), 4.33 (s, 2H), 7.38-7.47 (m, 2H), 7.54-7.63 (m, 3H), 8.03 (dd, 1H, J=7.8, 6.0 Hz), 8.14 (s, 1H), 8.36 (s, 1H), 8.48 (dd, 1H, J=8.1, 1.2 Hz), 8.79 (dd, 1H, J=5.7, 1.2 Hz); 13C NMR (D2O) δ 16.99, 17.50, 22.52, 24.92, 39.53, 53.74, 54.46, 54.73, 126.46, 129.58, 129.62, 130.23, 134.13, 136.97, 137.55, 138.16, 140.85, 141.09, 147.55, 148.07, 149.10, 150.39; ES-MS m/z 375 (M+H). Anal. Calcd. for C24H30N4.3.4HBr. 3.1H2O: C, 40.86; H, 5.66; N, 7.94; Br, 38.51. Found: C, 40.66; H, 5.89; N, 7.82; Br, 38.79.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[CH:2]=[CH2:3].O.O.Cl[Sn]Cl.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[NH2:17])[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1ccc([N+](=O)[O-])c(OCC=C)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCOC(=O)c1ccc(N)c(OCC=C)c1
Yield: 92.5 %

Procedure:
The crude ester (10 g, 38 mM) was dissolved in ethanol (20 ml) and added to a stirred suspension of SnCl2.2H2O (42.9 g, 0.19M) in ethanol (60 ml) under argon at ambient temperature. The mixture was heated to reflux for 30 minutes, cooled and poured onto ice. After making basic to pH 8 with an aqueous solution of sodium bicarbonate, the mixture was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO4 and evaporated to give allyl 3-allyloxy-4-aminobenzoate (8.2 g).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.C([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=O)C>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[CH:7][C:2]([N:29]5[CH2:33][CH2:32][NH:31][C:30]5=[O:34])=[N:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(Br)cn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(N3CCNC3=O)cn2)CC1
Yield: 51.3 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 243 and 1-acetylimidazolidin-2-one (72 mg) and by the reaction and treatment in the same manner as in Example 638, the title compound (78 mg) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[CH2:12][C@@H:13]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[CH2:12][C@@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Cc2cccc(F)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(C[C@@H]2CCNC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 121.7 %

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of tert butyl (R)-3-(3-fluorobenzyl)-pyrrolidine-1-carboxylate (Intermediate 99, 0.515 g) in DCM (10 mL) and the mixture was stirred for 1 hour at room temperature. The mixture was evaporated to dryness and the residue was partitioned between DCM and saturated aqueous NaHCO3. The organic extract was separated, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 3-(R)-(3-fluoro-benzyl)pyrrolidine (0.402 g) as an oil.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[Cl:22][C:23]1[C:28]2[C:29]([CH:32]([CH3:34])[CH3:33])=[N:30][NH:31][C:27]=2[CH:26]=[CH:25][N:24]=1>C(OCC)(=O)C>[Cl:22][C:23]1[C:28]2[C:29]([CH:32]([CH3:34])[CH3:33])=[N:30][N:31]([CH:6]3[CH2:5][CH2:4][CH2:3][CH2:2][O:1]3)[C:27]=2[CH:26]=[CH:25][N:24]=1
Reactant: CC(C)c1n[nH]c2ccnc(Cl)c12
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Product: CC(C)c1nn(C2CCCCO2)c2ccnc(Cl)c12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Dihydropyran (10.0 mL) and (+)-10-camphorsulfonic acid (0.062 g) were sequentially added to compound (4a) (0.55 g), followed by stirring at 80° C. for 30 min. After cooling, the reaction solution was distributed between ethyl acetate and a saturated aqueous sodium bicarbonate solution, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain 4-chloro-3-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.727 g, 93%) as a colorless oily substance. Subsequently, tetrakis(triphenylphosphine)palladium(0) (0.149 g) was added to a solution of the colorless oily substance (0.727 g), quinoline-3-boronic acid (0.539 g), and an aqueous sodium carbonate solution (1 M, 13 mL) in ethylene glycol dimethyl ether (26 mL) under a nitrogen atmosphere at 85° C. for 25 hr. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After distillation of the solvent, THF (5.2 mL) and concentrated hydrochloric acid (2.6 mL) were added to the residue, followed by stirring at 60° C. for 1 hr. The pH was adjusted to 7 with an aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain compound (4b) (0.395 g, the third yield: 52%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[C:12]1([NH:11][C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: S=C=NCc1ccccc1
Solvent: Cc1ccccc1
Product: S=C(NCc1ccccc1)Nc1ccccc1

Procedure:
To a stirred solution of 74.6 g (0.5 mol) of benzylisothiocyanate in 500 mL toluene was added dropwise 46.6 g (0.5 mol) of aniline. The solution was refluxed 18 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from an appropriate solvent to yield N-phenyl-N'-benzylthiourea. Isothiocyanates which are not commercially available may be prepared from aliphatic or aryl primary amines by the following methods: Kurita and Iwakura, Org. Synth. 59, 195; Jochims, Chem. Ber. 101, 1746 (1968); or Castro, Pena, Santos, and Vega, J. Org. Chem. 49, 863 (1984).