Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.Cl.[F:10][C:11]([F:34])([F:33])[C:12]([NH:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[NH:29][CH:30]=[CH:31][C:24]=23)=[C:17]([F:32])[CH:16]=1)=[O:13]>O1CCCC1>[Cl:1][C:31]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][C:23]=2[O:22][C:18]2[C:19]([F:21])=[CH:20][C:15]([NH:14][C:12](=[O:13])[C:11]([F:10])([F:33])[F:34])=[CH:16][C:17]=2[F:32])[NH:29][CH:30]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(Nc1cc(F)c(Oc2ccnc3[nH]ccc23)c(F)c1)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Nc1cc(F)c(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
204 mg (1.54 mmol) of N-chlorosuccinimide and 50 μl of 1M aqueous hydrochloric acid are added to a solution of 250 mg (0.70 mmol) of 2,2,2-trifluoro-N-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]acetamide in anhydrous tetrahydrofuran (5 ml). The solution is stirred at RT overnight. The title compound precipitates from the reaction mixture. A solid is obtained by filtration with suction and drying.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][C@H:10]([O:22][CH3:23])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:14][CH2:13]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:19]1([CH2:18][N:15]2[CH2:14][CH2:13][N:12]([CH2:11][C@@H:10]([O:22][CH3:23])[CH2:9][NH2:8])[CH2:17][CH2:16]2)[CH2:20][CH2:21]1
Reactant: CO[C@H](CN1CCN(CC2CC2)CC1)CN(Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CO[C@@H](CN)CN1CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 106.9 %

Procedure:
(2S)—N,N-Dibenzyl-3-[4-(cyclopropylmethyl)piperazin-1-yl]-2-methoxy-propan-1-amine 35c (500 mg, 1.23 mmol) was dissolved in 30 mL of methanol followed by the addition of palladium/carbon (100 mg, 10%), filled with hydrogen for three times. The reaction mixture was stirred at room temperature for 12 hours and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (2S)-3-[4-(cyclopropylmethyl)piperazin-1-yl]-2-methoxy-propan-1-amine 35d (299 mg) as a yellow oil liquid, which was used in the next step without further furification.
Reaction SMILES: [H-].[Na+].C(S)C.C[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([CH2:16][CH2:17][CH3:18])[CH:15]=1)[CH:11]=[O:12]>CN(C=O)C>[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([CH2:16][CH2:17][CH3:18])[CH:15]=1)[CH:11]=[O:12]
Reactant: CCCc1cc(C=O)cc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: CCCc1cc(O)cc(C=O)c1

Procedure:
To a solution of sodium hydride (183 mg) and ethanethiol (0.6 ml) in DMF (15 ml) was added dropwise a solution of 3-methoxy-5-propyl-benzaldehyde (0.9 g). The reaction mixture was heated for 3 hours at 150°, quenched with NH4OAc buffer and extracted with ethyl ether. The ethyl ether layer was dried (Na2SO4) and evaporated. Flash chromatography of the residue using 30% ether in hexane afforded the title compound.
Reaction SMILES: Cl.[C:2]([O:6][CH2:7][C@@H:8]([C:10]([O:12][CH3:13])=[O:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(O)(=O)C.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([BH3-])#N.[Na+]>CO>[CH2:18]([NH:9][C@H:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:6][C:2]([CH3:5])([CH3:4])[CH3:3])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H](N)COC(C)(C)C
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H](COC(C)(C)C)NCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.5 %

Procedure:
Methyl O-tert-butyl-L-serinate hydrochloride (12 g, 56.7 mmol) was dissolved in methanol (120 ml), acetic acid (6.50 ml, 114 mmol), benzaldehyde (6.25 ml, 61.8 mmol), and sodium cyanoborohydride (1 M tetrahydrofuran solution, 75 ml) were added and the resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated, diluted with water, and neutralized with sodium bicarbonate under ice cooling, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, then the drying agent was removed by filtration and the solvent was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography [ethyl acetate:n-hexane=1:4 (v/v)] to give the title compound (7.75 g, 52%) as a colorless solid.
Reaction SMILES: [NH:1]([C:3]([CH2:5][NH:6][C:7]([C:9]1[C:10]2[CH:17]=[N:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:11]=2[CH:12]=[N:13][CH:14]=1)=[O:8])=O)[NH2:2].[CH3:25][N:26]=[C:27]=[S:28]>CCO>[CH3:25][NH:26][C:27]1[S:28][C:3]([CH2:5][NH:6][C:7]([C:9]2[C:10]3[CH:17]=[N:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C:11]=3[CH:12]=[N:13][CH:14]=2)=[O:8])=[N:1][N:2]=1
Reactant: NNC(=O)CNC(=O)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: CN=C=S
Solvent: CCO
Product: CNc1nnc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid hydrazinocarbonylmethyl-amide (104 mg, 0.32 mmol) in EtOH (4 mL) was added methyl isothiocyanate (50 mg, 0.7 mmol). The mixture was warmed at reflux for 6 days, and was then cooled to room temperature, and the product was collected by filtration. The crude material was suspended in concentrated sulfuric acid (1 mL) and stirred for 10 minutes. After standing for 10 minutes, the mixture was poured into ice water. The solution was made basic by addition of aqueous ammonia followed by a minimal amount of saturated aqueous sodium bicarbonate to pH=8 and the solid collected by filtration to afford title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C:9](=[O:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23].[BH4-].[Na+]>CO.O>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C@H:9]([OH:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23]
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)[C@H](O)[C@@H](c1ccccc1)N3
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3
Temperature: -2.5 °C
Reaction time: 0.17 h

Procedure:
6 g (19.52 mmol) of (8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetra-hydroimidazo-[1,2-h][1,7]naphthyridin-7-one (ee>90%, Daicel Chiralcel HPLC) are suspended in 60 ml of methanol and cooled to −5 to 0° C. in a methanol-ice bath. At this temperature, sodium borohydride (0.81 g, 21.47 mmol) is added by spatula during the course of 0.5 h (evolution of gas). After addition is complete, the mixture is stirred for a further 10 min, and then concentrated in a vacuum rotary evaporator at a bath temperature of 40° C. The oily residue obtained is taken up in distilled water and extracted three times with chloroform. The organic phases are combined and washed with a little water, then dried using anhydrous sodium sulfate and filtered. The filtrate is concentrated on a vacuum rotary evaporator and co-evaporated with acetone; the title compound crystallizes out in the course of this. The precipitate is filtered off, washed with acetone and dried to constant weight at 50° C. in a vacuum drying oven. 5.15 g (85.3%, ee>90%, Daicel Chiralcel HPLC) of the title compound are obtained as a colorless crystallizate of melting point 206-9° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8]/[C:9](=[C:12]1\[CH2:13][O:14][C:15]2[C:20]([C:21]\1=[O:22])=[CH:19][C:18]([F:23])=[CH:17][CH:16]=2)/SC.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCOCC>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8]/[C:9](=[C:12]1\[CH2:13][O:14][C:15]2[C:20]([C:21]\1=[O:22])=[CH:19][C:18]([F:23])=[CH:17][CH:16]=2)/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CS/C(CCC1OCCCO1)=C1/COc2ccc(F)cc2C1=O
Solvent: CCOCC
Product: O=C1/C(=C(/CCC2OCCCO2)c2ccccc2)COc2ccc(F)cc21
Reaction time: 0.5 h

Procedure:
To a solution of 650 mg (1.92 mmol) 5-2 in 50 mL of Et2O cooled to 0° C. was added dropwise 670 μL (2.02 mmol) 3M PhMgBr in Et2O. This mixture was stirred for 30 min, quenched with a solution of saturated NH4Cl, dumped into a separatory funnel containing EtOAc, the layers were separated, and the organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography with EtOAc/hexanes to provide 5-3 as a yellow oil. Data for 5-3: 1HNMR (500 MHz, CDCl3) δ 7.65 (m, 1H), 7.5-7.3 (m, 4H), 7.15 (m, 2H), 6.85 (m, 1H), 4.8 (s, 2H), 4.55 (m, 1H), 4.05 (m, 2H), 3.7 (m, 2H), 3.0 (m, 2H), 2.0 (m, 1H), 1.7 (m, 2H), 1.3 (m, 1H) ppm, LC-MS: rt=2.9 min, m/z=369 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:15][C:16]([O:18][CH3:19])=[O:17]>>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: O=C1CC[C@@H](c2ccc(O)cc2)C1
Product: COC(=O)COc1ccc([C@@H]2CCC(=O)C2)cc1
Yield: 100.7 %

Procedure:
(R)-3-(4-Hydroxyphenyl)cyclopentanone (0.82 g, 4.6 mmol) and methyl bromoacetate (0.9 mL, 10 mmol) were used and treated in a similar manner to (Step 4) of (Example 10) to give the title compound (1.15 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:15].[H][H]>[C].[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc(C(=O)CCC(=O)O)ccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(CCCC(=O)O)ccc1F
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 87.8 %

Procedure:
In a 50-ml autoclave, 1.0 g of 4-(4-fluoro-3 -methylphenyl)-4-oxobutanoic acid and 2.5 ml of methanol were charged, followed by the addition of 0.1 g of 10% palladium-carbon. After hydrogen pressure was increased to 30 kg/cm2 at room temperature, the resulting mixture was stirred at 50° C. for 3.5 hours. After the completion of the reaction, the reaction mixture was filtered, followed by washing with methanol. The filtrate was thereafter concentrated under reduced pressure. Water was added to the residue so obtained. The crystals so precipitated were filtered, washed with water and dried under reduced pressure, whereby 0.82 g of the title compound was obtained.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH:20]=[C:19]([C:21]5[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=5)[NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>CN(C=O)C>[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH:20]=[C:19]([C:21]5[CH2:22][CH2:23][N:24]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:25][CH:26]=5)[NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: CS(=O)(=O)Cl
Reactant: C1=C(c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)CCNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CC=C(c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)CC1
Reaction time: 8 h

Procedure:
(1H-Indazol-5-yl)-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine hydrochloride (80 mg, 0.217 mmol), Hunigs base (113 μL, 0.653 mmol) and methanesulfonyl chloride (17 μL, 0.2177 mmol) were combined in DMF at rt and stirred overnight. The reaction was concentrated in vacuo and residue purified on silica gel by elution with tetrahydrofuran:dichloromethane (3:2) to yield the title compound as white solid. 1H NMR (d6-DMSO, 400 MHz) 9.4(1H, br. s), 8.4 (1H, s), 8.3(1H,s), 8.0(1H,s), 7.7(1H, d), 7.5(1H, d), 6.8(1H, s), 6.4(1H,s), 3.9(2H, s), 3.4(2H, m), 3.0(3H,s) and 2.6(2H, s); LC/MS: m/z 410 [M+H]+, Rt=2.82 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([NH:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:4][N:3]=1
Reactant: NC1CCCCC1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Product: Cc1cccc2c(Cl)ncc(C(=O)NC3CCCCC3)c12

Procedure:
This compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and cyclohexylamine by following the similar procedure as described for intermediate-11a.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]=[C:9]=[S:10])[CH:3]=1.[NH3:11]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: S=C=Nc1cccc(Cl)c1
Solvent: C1COCCO1
Product: NC(=S)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.16 h
Yield: 89 %

Procedure:
1-Chloro-3-isothiocyanatobenzene (15 g, 88 mmol) was added to a solution of 0.5 M ammonia in 1,4-dioxane (80 mL), and the mixture was stirred at room temperature for 0.16 h. The reaction mixture was concentrated in vacuo, and partitioned between ethyl acetate and water. The separated organic layer was washed with saturated NaCl solution, dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo to afford the title compound (15.5 g, 89%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.70 (s, 1H), 7.52 (bs, 2H), 7.38-7.27 (m, 2H), 7.15 (dt, J1=7.0 Hz, J2=2.1 Hz, 1H). ESI-MS m/z: 187 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:22]([OH:24])=[O:23])[S:12][C:13]=2[C:14]2[CH:19]=[C:18](F)[CH:17]=[C:16](Cl)[CH:15]=2)[CH:5]=[CH:6][C:7]=1F.BrC1SC(C(OCC)=O)=[N:28][C:27]=1C1C=CC=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:22]([OH:24])=[O:23])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:27]#[N:28])[CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(-c2ccc(F)c(Cl)c2)c(-c2cc(F)cc(Cl)c2)s1
Reactant: CCOC(=O)c1nc(-c2cccc(Cl)c2)c(Br)s1
Product: N#Cc1cccc(-c2sc(C(=O)O)nc2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 8A starting with the compound from Example 5A. 556 mg of the title compound having a purity of 41% (46% of theory) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11e, and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.80 (d, 1H), 8.05 (m, 1H), 7.84 (m, 3H), 7.43 (m, 1H), 7.34 (d, 1H), 7.15 (m, 3H), 7.06 (d, 1H), 6.91 (d, 1H), 6.86 (s, 1H), 4.39 (s, 2H), 4.36 (s, 2H), 3.65 (s, 3H), 2.82 (t, 2H), 2.51 (t, 2H); MS 508 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1>CC(O)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:17]=2[CH:18]=1)=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3
Reactant: COc1ccc(Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc2[nH]c3ccc([N+](=O)[O-])cc3c2c1
Temperature: 100 °C
Yield: 63.9 %

Procedure:
To 4-methoxy-N-(4-nitrophenyl)aniline (785 mg, 3.2 mmol) in 5 mL of AcOH was added Pd(OAc)2 (1.43 g, 6.4 mmol). The mixture was heated at 100° C. for 15 h under air atmosphere and cooled to rt and concentrated under reduced pressure. The residue was taken up in EtOAc (100 mL) and washed with NaHCO3 (2×100 mL) and water (100 mL). After solvent removal, the crude was purified with chromatography (hexane/EtOAc) to afford 3-methoxy-6-nitro-9H-carbazole as a orange solid (495 mg, 64%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCC/C=C\c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [Pd]
Solvent: CCO
Product: CCCCCc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Yield: 88.4 %

Procedure:
To a solution of 2-[3-methyl-2-((Z)-pent-1)-enyl-benzoylamino]-indan-2-carboxylic acid ethyl ester (124) (92 mg, 0.23 mmol) in absolute EtOH (10 mL) is added the catalyst, Pd—C (50% wetted powder, 10% Pd, 30 mg, 1.4% mmol) under argon. The resulting reaction mixture is moved to the Paar apparatus to run hydrogenation: 50 psi, room temperature, overnight. The catalyst is removed by the filtration through a pre-column (10 g silica gel) and washed by EtOH. The combined EtOH solution is concentrated in vacuo. The residue is purified by HPLC to give a pure product (126) as white solid (80 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]([OH:12])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[H-].[Na+].[CH3:15]I>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]([O:12][CH3:15])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CI
Reactant: OC1CCCc2nc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CCCc2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 61 %

Procedure:
To a solution of 2-chloro-5,6,7,8-tetrahydroquinolin-5-ol (319 mg, 1.737 mmol) in tetrahydrofuran (8 mL) was added in small portions sodium hydride (83 mg, 2.085 mmol; 60 on mineral oil). After stirring the resulting suspension for 20 min at RT methyl iodide (0.119 ml, 1.911 mmol) was added dropwise. The reaction mixture was stirred at RT for 20 h. The reaction was quenched by addition of a saturated ammonium chloride solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine and dried over sodium sulfate, filtered, and evaporated to dryness. The crude was purified by flash chromatography (silica gel, cyclohexane/ethylacetate) yielding a slightly yellow oil. Amount 210 mg. Yield 61%.
Reaction SMILES: [CH2:1]([PH:8](=[O:10])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:23]([O:30][C:31]([CH:33]([CH2:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[CH2:34]P(C)(=O)OCC1C=CC=CC=1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:1]([P:8]([CH2:34][CH:33]([C:31]([O:30][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:32])[CH2:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:49])(=[O:9])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[PH](O)Cc1ccccc1
Reactant: CP(=O)(CC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCC(CP(=O)(O)Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
Benzylphosphinic acid (2.3 g, 15 mmol) in 150 mL of dry dichloromethane was cooled to 0° C. under a nitrogen atmosphere. Triethylamine (6.5 g, 65 mmol) was added followed by trimethylsilyl chloride (5.8 g, 54 mmol) while the reaction temperature was maintained at 0° C. After 30 minutes dibenzyl 2-methylenepentanediote (2) in 20 mL of dichloromethane was added over 5 minutes. The reaction mixture was left to warm to room temperature and stirred overnight. The clear solution was cooled to 0° C. and quenched with 5% hydrochloric acid and with brine, dried (MgSO4) and evaporated to give a clear yellow liquid. Purification by flash chromatography and elution with 1:1 hexane/ethyl acetate containing 10% acetic acid yielded 2.0 g (28%) of benzyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (3, R=CH2Ph, R1+H) as a clear light yellow oil. Rf 0.37 (1:1 Hex./EtOAc, 10% AcOH).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=1[NH2:16].C(N(CC)CC)C.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>>[CH3:7][C:4]1[CH2:5][CH:6]=[C:2]([CH3:1])[C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1=CCC(C)=C1c1c(C)cc(C)cc1N
Solvent: CCN(CC)CC
Product: CC1=CCC(C)=C1c1c(C)cc(C)cc1NC(=O)C(C)(C)C
Yield: 69.8 %

Procedure:
0.717 g (3.36 mmol) of 2-(2,5-dimethylcyclopenta-1,4-dienyl)-3,5-dimethylphenylamine, 0.408 g (4.03 mmol) of triethylamine, and 0.486 g (4.03 mmol) of pivaloyl chloride were used in the same manner as in Example 11. The resultant reaction product was purified using a column chromatography using a toluene/MC (v/v, 1:1) solvent, and then the solvent in the purified product was removed in vacuum, thereby obtaining while solid (0.698 g, 70%).
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:21]([C:3]([S:4][C:5]3[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)=[C:2]([CH3:15])[NH:24]2)=[CH:22][CH:23]=1
Reactant: CC(=O)CSc1ccc(CC(=O)O)cc1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: Cc1[nH]c2cc(Cl)ccc2c1Sc1ccc(CC(=O)O)cc1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [4-(2-oxo-propylsulfanyl)-phenyl]-acetic acid and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:27])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([OH:26])[CH:19]=2)[O:16][CH:17]=1)[CH3:2].N12CCCN=C1CCC[CH2:30][CH2:29]2.C(I)C>C(O)C>[CH2:29]([O:26][C:20]1[CH:19]=[C:18]([C:15]2[O:16][CH:17]=[C:13]([CH2:12][CH2:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH2:1][CH3:2])=[O:27])[N:14]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25])[CH3:30]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(O)c2)n1
Solvent: CCI
Solvent: CCO
Product: CCOc1cc(-c2nc(CCC(=O)c3ccccc3OCC)co2)ccc1OC
Reaction time: 4 h

Procedure:
A 0.3 g quantity of 1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one obtained in Example 101 was suspended in 10 ml of ethanol, 0.37 g of 1,8-diazabicyclo[5,4,0]undec-7-ene and 0.26 g of ethyl iodide were added thereto, and the suspension was stirred for 4 hours while heating and refluxing. After distilling off ethanol under reduced pressure, water was added, ethyl acetate extraction was performed, followed by drying over anhydrous magnesium sulfate and distilling the solvent off. The residue was subjected to silica gel column purification (n-hexane:ethyl acetate=3:1), thereby yielding 0.15 g of white powdery 3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNCC1
Reactant: O=Cc1cccc(O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Oc1cccc(CN2CCCCC2)c1Cl

Procedure:
In a similar manner to that described in Example 17 2-chloro-3-hydroxybenzaldehyde (9 g) in absolute ethanol (60 ml) was treated with piperidine (11.7 ml) and sodium borohydride (2.2 g) to yield N-(2-chloro-3-hydroxybenzyl)piperidine. The piperidine thus prepared was reacted with 4-bromobutyronitrile to give 4-(2-chloro-3-piperidinomethylphenoxy)butyronitrile.