Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[C:44](=[O:46])=[O:45]>C1COCC1>[Br:15][C:13]1[CH:14]=[C:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]([F:16])=[C:11]([CH:12]=1)[C:44]([OH:46])=[O:45]
Reactant: Fc1ccc(Br)cc1N(Cc1ccccc1)Cc1ccccc1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(Br)cc(N(Cc2ccccc2)Cc2ccccc2)c1F
Reaction time: 0.75 h
Yield: 40 %

Procedure:
Add dropwise a solution of dibenzyl-(5-bromo-2-fluorophenyl)-amine (4.00 g, 10.8 mmol) in THF (12 mL) to a solution of lithium diisopropylamide, freshly prepared by adding n-butyllithium (1.6 M in hexanes, 7.09 mL, 11.3 mmol) to diisopropylamine (1.74 mL, 12.4 mmol) in THF (25 mL) at −78° C. Stir the resulting yellow solution at −78 C for 45 min. Pour into a dry ice slurry containing about 100 g in dry THF (40 mL). Stir the solution until it reaches room temperature. Concentrate the solution and dissolve the residue in 10% aqueous potassium hydroxide solution (40 mL) and extract with diethyl ether (70 mL). Acidify the aqueous layer to about pH=3 with concentrated HCl. Extract the aqueous layer with diethyl ether (2×200 mL). Combine the organic layers and wash with water (150 mL), dry (magnesium sulfate) and concentrate to give the title compound as a solid (1.81 g, 40%).
Reaction SMILES: F[C:2]1(F)[C:11]2[C:6](=[CH:7]C=C[CH:10]=2)[C:5](=[O:12])[C:4]([C:13](F)(F)F)=[CH:3]1.F[C:19]1(F)C2C(=CC=CC=2)C(F)(F)C=C1C(F)(F)F>CC(C)=O>[CH3:13][C:4]1[C:3]([CH3:19])=[CH:2][C:11]([CH3:10])=[C:6]([CH3:7])[C:5]=1[OH:12]
Reactant: O=C1C(C(F)(F)F)=CC(F)(F)c2ccccc21
Reactant: FC(F)(F)C1=CC(F)(F)c2ccccc2C1(F)F
Solvent: CC(C)=O
Product: Cc1cc(C)c(C)c(O)c1C

Procedure:
Anal. Calcd. for C30H39F3OS2 : C, 67.16; H, 7.28; F, 10.63; S, 11.94. Found (A): C, 63.64; H, 5.37; F, 12.85; S, 7.69; MW, 2737; Found (B): C, 67.62; H, 5.37; F, 11.62; S, 11.80; MW, 5785; Found (C); C, 65.00; H, 5.72; F, 12.61; S, 12.98; MW, 928;
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:17][C:11]1([C:14]([OH:16])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C(=O)O)CCNCC1
Yield: 99.7 %

Procedure:
1-(tert-Butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (0.500 g, 2.06 mmol) was treated with 4 M HCl in dioxane (10 mL) for 2 hours at room temperature to afford the title compound (0.294 g, 100%) as the hydrochloride salt. MS (ES+) [M+H]+=144.0.
Reaction SMILES: [N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10](OC)=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[OH:11][CH2:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[N:2][N:1]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2cnn(C(=O)OC(C)(C)C)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)n1ncc2ccc(CO)cc21
Reaction time: 1.5 h
Yield: 14.6 %

Procedure:
A solution of 1-tert-butyl 6-methyl 1H-indazole-1,6-dicarboxylate (766 mg, 2.76 mmol) in anhydrous THF (11 mL) was cooled to −30° C., LiAlH4 (210 mg, 5.53 mmol) was added in portions below −30° C., and the mixture was stirred at this temperature for 1.5 h, added water: 10% NaOH:water=0.8 mL:2.4 mL:0.8 mL carefully, filtered, and the filtrate was concentrated and purified by silica gel chromatograph to afford 100 mg of the title compound (14%). 1H NMR (400 MHz, CDCl3): δ 1.72 (9H, s), 4.86 (2H, s), 7.33 (1H, d, J=8.0 Hz), 7.69 (1H, d, J=8.4 Hz), 8.13 (1H, s), 8.21 (1H, s). [M+H] Calc'd for C13H16N2O3, 249. Found, 249.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][OH:15].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][O:15][C:17]1[O:16][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: C1=COCCC1
Reactant: OCCCc1ccc2ccccc2c1Br
Solvent: ClCCl
Product: Brc1c(CCCOC2=CCCCO2)ccc2ccccc12
Yield: 95.9 %

Procedure:
A mixture of Example 10A (2.96 g, 11.2 mmol) and 3,4-dihydro-2H-pyran (2.04 mL, 22.4 mmol) in CH2Cl2 and was stirred at 0° C. for 10 minutes and at room temperature for 40 minutes. The reaction mixture was partitioned between CH2Cl2 and water, the organic layer dried (Na2SO4), filtered, concentrated, and purified on silica gel with 10% ethyl acetate/hexanes to provide 3.73 g (95%) of the desired compound as an yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([OH:31])[CH2:26]1>ClCCl.O>[NH2:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][N:5]2[C:3](=[O:4])[CH2:2][N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([OH:31])[CH2:26]2)=[CH:9][C:10]=1[O:17][CH3:18]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CC2
Reactant: OC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1N)N(C(=O)CN1CCCC(O)C1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
The 1-(bromoacetyl)-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (4.0 g, 12.7 mmol) was dissolved in 50 mL of dichloromethane, then K2CO3 (4.4 g, 31.7 mmol) and 3-piperidinol (1.54 g, 15.2 mmol) in 10 mL dichloromethane were added, the reaction was stirred at RT overnight. The reaction mixture was diluted with 100 mL of water, the organic solvents were washed with water (2×100 mL), dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting residue was dissolved in 10 mL of EA, 25 mL of MeOH and 15 mL of THF, then 0.8 g 10% Pd/C was added, the reaction was stirred at RT overnight under balloon H2 pressure. The catalyst was removed via filtration and the solvent was removed under reduced pressure to yield 1-{2-[6-amino-5-(methyloxy)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-3-piperidinol as a white solid (3.0 g, 92%). 1HNMR (400 MHz, DMSO-d6) δ ppm: 1.09 (m, 1 H), 1.44 (m, 1 H), 1.62 (m, 1 H), 1.74 (m, 1H), 2.14(br, 1H), 2.47(s, 1H), 2.74(br, 2H), 2.95 (m, 4H), 3.50(s, 2H), 3.68(s, 3H), 4.04 (t, J=6.13 Hz,2 H), 4.71 (s, 2H), 6.68 (s, 1 H), 7.51 (s, 1 H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:14][C:13]2[CH:12]=[C:11]([C:10]#[C:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:18]=[CH:17][CH:16]=2)[CH2:23][CH2:22]1
Reactant: O=Cc1cccc(C#CCCN2CCOCC2)c1
Reactant: COC1CCNCC1
Product: COC1CCN(Cc2cccc(C#CCCN3CCOCC3)c2)CC1

Procedure:
May be prepared analogously to Example 15 using the product of Example 10 and 4-methoxypiperidine.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[O:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[Br:13]N1C(=O)CCC1=O>ClCCl>[C:1]([C:4]1[C:5](=[O:12])[O:6][C:7]([CH2:11][Br:13])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(O)cc(C)oc1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(=O)c1c(O)cc(CBr)oc1=O
Reaction time: 4.5 h
Yield: 47 %

Procedure:
A mixture of 3-acetyl-4-hydroxy-6-methylpyran-2-one (52 parts), N-bromosuccinimide (54 parts) and dichloromethane (1060 parts) were stirred at 20°-25° C. for about 4-5 hours under exposure to UV light. The dichloromethane solution was washed with water (2×500 cm3) to remove the succinimide, dried over magnesium sulphate, filtered and the solvent removed at 40° C./20 mm to leave 3-acetyl-6-bromomethyl-4-hydroxypyran-2-one (70 parts, 47%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:22]Br>>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cc(F)cc(F)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3,5-difluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=[CH:28][C:21]=34)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].[ClH:37]>C(Cl)Cl.O1CCOCC1>[CH3:35][Si:33]([CH3:34])([CH3:36])[CH2:32][CH2:31][O:30][CH2:29][N:26]1[C:22]2=[N:23][CH:24]=[CH:25][C:20]([C:18]3[CH:17]=[N:16][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:5][NH:6][CH2:7]4)[CH:19]=3)=[C:21]2[CH:28]=[CH:27]1.[ClH:37]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (1.6 g) in methylene chloride (10 mL) was added a solution of 4.0 M of hydrogen chloride in dioxane (20 mL). The mixture was stirred at room temperature overnight. Then it was concentrated under reduced pressure to afford the desired compound as HCl salt (1.5 g). LCMS (M+H)+: m/z=409.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:34])[C@H:30]([CH2:32][OH:33])[NH2:31])C.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:26][O:28][C:29](=[O:34])[CH:30]([NH:31][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:11])(=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:21]([F:22])([F:23])[F:24])[CH2:32][OH:33]
Reactant: CCOC(=O)[C@@H](N)CO
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C(CO)NC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.556 g (10 mmol) of L-serine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [C:1]1([C:7](=[O:16])[CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]Br>C(O)(=O)C>[Br:17][CH:8]([S:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:16]
Reactant: BrBr
Reactant: O=C(CSc1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: O=C(c1ccccc1)C(Br)Sc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-phenyl-2-(phenylthio)ethanone (2.1 g) in acetic acid (20 mL) was added bromine (0.5 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 2.9 g, about 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([NH2:33])[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:35](Cl)(=[O:37])[CH3:36]>CN(C1C=CN=CC=1)C.O1CCOCC1.C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][N:21]4[N:30]=[C:31]([NH:33][C:35](=[O:37])[CH3:36])[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(N)nn4cc3-c3ccccc3)cc2)CCC1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)Nc1nc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 100 °C
Yield: 58.3 %

Procedure:
To the solution of 6-1 (100 mg, 0.22 mmol) and Et3 N (0.2 mL) DMAP (2 mg) in dioxane (2 mL) was added acetyl chloride (21 mg, 0.25 mmol) and the mixture was heated at 100° C. for 10 h. The mixture was diluted with 20 mL of DCM, the combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 64 mg of 6-3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][C@@H:7]1[CH2:12][CH2:11][N:10](C)[CH2:9][C@H:8]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C1C=CC=CC=1>[CH2:33]([O:32][C:30]([N:10]1[CH2:11][CH2:12][C@@H:7]([O:6][C:5]2[CH:20]=[CH:21][CH:22]=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=[O:31])[CH3:34]
Reactant: CCOC(=O)Cl
Reactant: COc1cccc(O[C@@H]2CCN(C)C[C@H]2c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@@H](Oc2cccc(OC)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 0.45 g of trans-4-(3-methoxyphenoxy)-1-methyl-3-phenylpiperidine, 0.31 g of anhydrous potassium carbonate, 0.22 ml of ethyl chloroformate and 4 ml of anhydrous benzene is stirred for a few minutes at room temperature, then refluxed overnight. Another 0.11 ml of ethyl chloroformate is added, the mixture is refluxed for another 4 hours, then cooled and partitioned between 25 ml of ether and 25 ml of water. The aqueous phase is extracted with another 25 ml of ether, and the combined ether extracts are washed with 2 N hydrochloric acid (2×10 ml), saturated sodium chloride solution (25 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 0.37 g of product as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.O=[C:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH:15]1[C:20](OC)=[O:21]>>[CH3:3][C:1]([C:5]1[CH:10]=[CH:9][C:8]2[C:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[C:20](=[O:21])[O:11][C:7]=2[CH:6]=1)([CH3:4])[CH3:2]
Reactant: COC(=O)C1CNCCC1=O
Reactant: CC(C)(C)c1cccc(O)c1
Agent: Cl
Product: CC(C)(C)c1ccc2c3c(c(=O)oc2c1)CNCC3
Yield: 57.1 %

Procedure:
Prepared by the method described for Example 1 from 3-t-butylphenol (15 g, 0.1 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (19.3 g, 0.1 moles). Recrystallization from ethyl acetate gave the product (14.7 g), mp 181°-186° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([CH2:23][CH:24]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][C:19]=2[CH:37]=1)#[N:14].[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[CH2:50]O)=[O:44])([CH3:41])([CH3:40])[CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[CH2:50][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH:24]([CH2:23][C:21]2[O:22][C:18]3[CH:17]=[CH:16][C:15]([C:13]#[N:14])=[CH:37][C:19]=3[CH:20]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:35][CH:34]=1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
1.04 g of diethyl azodicarboxylate was added to 300 ml of a tetrahydrofuran solution containing 1 g of ethyl 3-(5-cyano-2-benzofuranyl )-2-(4-hydroxyphenyl)propionate, 1.2 g of (2S)-1-tert-butoxycarbonyl-2-pyrrolidinemethanol and 1.56 g of triphenylphosphine, and the thus prepared mixture was stirred at room temperature for 18 hours. To the resulting reaction solution were added 0.6 g of (2S)-1-tert-butoxycarbonyl-2-pyrrolidinemethanol, 0.78 g of triphenylphosphine and 0.52 g of diethyl azodicarboxylate, followed by additional stirring at room temperature for 18 hours. Thereafter, the reaction solution thus obtained was concentrated to dryness, and the resulting residue was purified by subjecting it to silica gel column chromatography using a toluene/ethyl acetate mixture as an eluant. In this way, 790 mg of the title compound was obtained in the form of colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[I:21]N1C(=O)CCC1=O>CN(C=O)C>[F:1][C:2]1[CH:8]=[C:7]([I:21])[CH:6]=[C:5]([F:9])[C:3]=1[NH2:4]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: Nc1c(F)cc(I)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.4 %

Procedure:
To a solution of 2,6-difluoroaniline (5.0 g, 38.7 mmol) and p-toluenesulfonic acid (1.45 g, 7.62 mmol) in DMF (70 mL) was added dropwise N-iodosuccinimide (9.6 g, 42.7 mmol) dissolved in DMF (50 mL) at 5° C. The mixture was stirred for 2.5 hours at room temperature. The mixture was concentrated under reduced pressure, and then diluted with EtOAc and water. The organic layer was washed with saturated aqueous sodium thiosulfate and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by crystallization from EtOAc and hexane to give 2,6-difluoro-4-iodoaniline (9.12 g, 92.4%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]([NH:15][C:16]([C:18]1[C:19]2[CH:26]=[N:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:20]=2[CH:21]=[N:22][CH:23]=1)=[O:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:6]=1.C(N(CC)C(C)C)(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([N:24]2[C:20]3[CH:21]=[N:22][CH:23]=[C:18]([C:16]([NH:15][C@H:4]([C:5]4[CH:10]=[CH:9][N:8]=[C:7]([S:11]([CH3:14])(=[O:12])=[O:13])[CH:6]=4)[CH2:3][CH2:2][O:1][S:44]([CH3:43])(=[O:46])=[O:45])=[O:17])[C:19]=3[CH:26]=[N:25]2)=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)c1cc([C@H](CCO)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(C)(=O)=O)c1
Reaction time: 0.08 h

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid[(S)-3-hydroxy-1-(2-methanesulfonyl-pyridin-4-yl)-propyl]-amide (0.10 g, 0.21 mmol) and N,N-diisopropylethylamine (167 μL, 0.957 mmol) in dichloromethane (20 mL) was cooled in an ice water-brine bath. After 5 minutes, methanesulfonyl chloride (25 μL, 0.32 mmol) was added and the cold bath was removed until the mixture became homogeneous. The mixture was again cooled in an ice bath. After 30 minutes, the mixture was quenched with saturated aqueous ammonium chloride (10 mL), washed with brine (10 mL), dried over magnesium sulfate and concentrated to afford methanesulfonic acid(S)-3-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-3-(2-methanesulfonyl-pyridin-4-yl)-propyl ester which was used without further purification.
Reaction SMILES: [C:1]([OH:4])(=[O:3])C.[OH:5][CH2:6][C:7]1[CH:18]=[CH:17][C:10]([C:11]([NH:13][CH2:14][CH2:15][NH2:16])=[O:12])=[CH:9][CH:8]=1>CO>[C:7]([O:4][C:1]([NH:16][CH2:15][CH2:14][NH:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][OH:5])=[CH:18][CH:17]=1)=[O:3])([CH3:18])([CH3:8])[CH3:6]
Reactant: NCCNC(=O)c1ccc(CO)cc1
Reactant: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(CO)cc1

Procedure:
p-Hydroxymethylbenzoylaminoethylamine acetate (0.30 g, 1.2 mmol) in methanol was treated with di-t-butyloxycarbonyl dicarbonate (0.38 g, 1.8 mmol). The solvent was evaporated, and the residue was dissolved in ether. The ether solution containing the product was filtered and reduced in volume leaving a white solid, which was removed by filtration and washed with petroleum ether. Yield 0.34 g (99%). Mp 117°-119°.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15](=[N:17]O)[CH3:16])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.N.[Ni]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:16])[NH2:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(C)=NO)cc1OC1CCCC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1ccc(C(C)N)cc1OC1CCCC1
Yield: 100.1 %

Procedure:
A solution of 1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone oxime (15.3 g) in methanol/ammonia (350 ml) was hydrogenated for 3 hours with Raney nickel (3 g) as a catalyst. After uptake of H2, the catalyst was filtered off, washed with methanol and the filtrate was evaporated. Toluene was added and azeotroped on the rotary evaporator, yielding 14.45 g (100%) of (±)-3-(cyclopentyloxy)-4-methoxy-α-methylbenzenemethanamine (interm. 5).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:16][CH2:15][O:14][C:5]2=[C:6]([C:12]=1[NH2:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:17]N1C(=O)CCC1=O>>[CH2:10]([O:9][C:7](=[O:8])[C:6]1[C:12]([NH2:13])=[C:2]([Cl:17])[CH:3]=[C:4]2[O:16][CH2:15][O:14][C:5]=12)[CH3:11]
Reactant: CCOC(=O)c1c(N)c(Br)cc2c1OCO2
Reactant: O=C1CCC(=O)N1Cl
Product: CCOC(=O)c1c(N)c(Cl)cc2c1OCO2
Yield: 75 %

Procedure:
Following the procedure employed in Example 27, treatment of ethyl 5-bromo-2,3-methylenedioxy-6-aminobenzoate with N-chlorosuccinimide instead of N-bromosuccinimide, gave the title compound in 75% yield after silica gel chromatography, mp 77°-78° C.
Reaction SMILES: Cl.[C:2]([C:5](=[N:10][O:11][CH2:12][CH3:13])[C:6]([O:8][CH3:9])=[O:7])(=[NH:4])[NH2:3].Cl[C:15](=[CH2:18])[C:16]#[N:17].C(N(CC)CC)C>C(O)C>[CH2:12]([O:11][N:10]=[C:5]([C:2]1[N:3]=[C:16]([NH2:17])[CH:15]=[CH:18][N:4]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:13]
Reactant: C=C(Cl)C#N
Reactant: CCON=C(C(=N)N)C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCON=C(C(=O)OC)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A mixture of methyl 2-amidino-2-ethoxyiminoacetate hydrochloride (syn isomer) (2.1 g), 2-chloroacrylonitrile (875 mg) and triethylamine (2.0 g) in ethanol (21 ml) was stirred for 8 hours at ambient temperature and allowed to stand at the same temperature overnight. The mixture was evaporated to dryness and the residue was dissolved in a mixture of ethyl acetate (20 ml) and water (10 ml). The organic layer was separated out, treated with activated charcoal and evaporated to dryness. The residue was purified by a column chromatography on silica gel (30 g) using ethyl acetate-benzene (1:1) as an eluant to give a mixture (1.0 g) of methyl 2-ethoxyimino-2-(4-aminopyrimidin-2-yl)acetate (syn isomer) and ethyl 2-ethoxyimino-2-(4-aminopyrimidin-2-yl)acetate (syn isomer) (1:1). mp 105° to 110° C.