Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][N:15]=[N+]=[N-])[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][NH2:15])[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2
Reactant: [N-]=[N+]=NCCOc1cc(F)cc2c1OCCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCOc1cc(F)cc2c1OCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
A solution of 2-(6-fluorochroman-8-yloxy)ethylazide (4.12 g, 0.017 mol) and triphenylphosphine (6.83 g, 0.026 mol) in tetrahydrofuran (80 ml) and water (1.5 ml) was allowed to stir for 18 hours at room temperature. The solvent was removed under vacuum. Chromatography (ethyl acetate) removed triphenylphosphine and triphenylphosphine oxide and (40% methanol-methylene chloride plus ammonium hydroxide) afforded 3.45 g (94%) of product as a white solid: mp 68-70° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([OH:11])/[CH:8]=[CH:9]/[I:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]1([C:18](Br)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([O:11][C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)/[CH:8]=[CH:9]/[I:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC(/C=C/I)CC1CCCC1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: I/C=C/C(CC1CCCC1)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 21.4 g. of 4-cyclopentyl-1-iodo-trans-buten-3-ol (Example 34) in 170 ml. of dry pyridine containing 31 g. of triphenylmethyl bromide is heated on the steam bath for 2 hours. The dark mixture is poured into 850 ml. of iced water and the resulting solution is extracted three times with ether. The combined extracts are washed with ice cold 2% hydrochloric acid until the washings are acidic, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Trituration of the residue followed by filtration removes triphenylcarbinol. The mother liquor is taken to dryness and the residual syrup is chromatographed on 400 g. of florisil using hexane gives 32 g. (78%) of syrup which solidifies on standing. Recrystallization from hexane affords white crystals, m.p. 87°-88° C.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]([CH3:34])[C:16]([C:18]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:19]=1)=[O:17])[CH:8]=[CH:7]2>C(O)(=O)C.C(OCC)(=O)C.C(O)(C)C>[Br:1][C:5]1[C:4]([OH:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH2:14][N:15]([CH3:34])[C:16]([C:18]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:19]=1)=[O:17])=[CH:10]2
Reactant: BrBr
Reactant: CN(Cc1ccc2cc(O)ccc2c1)C(=O)c1cn(Cc2ccccc2)c2ccccc12
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CN(Cc1ccc2c(Br)c(O)ccc2c1)C(=O)c1cn(Cc2ccccc2)c2ccccc12
Reaction time: 8 h
Yield: 215.1 %

Procedure:
A solution of bromine (0.37 mL, 0.7134 mmol) in 60 mL glacial acetic acid was added dropwise under nitrogen over 2 h to a solution of 1-benzyl-1H-indole-3-carboxylic acid (6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (3.0 g, 0.713 mmol), prepared in the previous step, in 300 mL glacial acetic acid at room temperature. The reaction stirred for 18 h (overnight). The solvent was removed under reduced pressure. The resulting residue was diluted with ethyl acetate and extracted with 5% sodium bicarbonate. A solid precipitated from the organic layer and was collected by filtration. The filtrate was dried (MgSO4) and concentrated under reduced pressure to give a tan solid. The two solids were combined and taken up in a mixture of ethyl acetate and isopropanol. A certain amount of material (1.0 g) would not dissolve upon heating and was removed by filtration. The filtrate was allowed to cool and upon cooling crystals formed. The crystals were collected by filtration and dried under reduced pressure to give 1-benzyl-1H-indole-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (0.766 g, 22%) as a tan solid, mp 181-182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CCNCC
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Solvent: Cc1ccccc1
Product: CCN(CC)c1cc(Cl)c([N+](=O)[O-])cc1F
Reaction time: 1 h
Yield: 88 %

Procedure:
A solution of 4.8 g (25 mmol) of 2-chloro-4,5-difluoronitrobenzene in 14.4 g of toluene are introduced into a 100 ml three-necked flask fitted with dropping funnel, precision-ground glass stirrer and reflux condenser. 5.7 g (78 mmol) of diethylamine are added dropwise to this solution at room temperature and with stirring over the course of 1 hour. The mixture is then stirred at room temperature for a further 2 hours. The reaction solution formed in the reaction is washed three times with 35 ml of water in each case and dried. The solvent is removed to give 5.4 g (22 mmol) of 2-chloro-4-diethylamino-5-fluoronitrobenzene. This corresponds to a yield of 88%, based on 2-chloro-4,5-difluoronitrobenzene used.
Reaction SMILES: [C:1]([O:11]C)(=O)/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]([O:8][CH3:9])=[O:7].[CH:13]1([O:19][N:20]2[C:25]([CH3:27])([CH3:26])[CH2:24][CH:23]([OH:28])[CH2:22][C:21]2([CH3:30])[CH3:29])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[NH2-:31].[Li+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:6]([O:8][CH:9]1[CH2:27][C:25]([CH3:24])([CH3:26])[N:31]([O:19][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:21]([CH3:30])([CH3:29])[CH2:22]1)(=[O:7])/[CH:5]=[CH:4]/[CH:3]=[CH:2]/[C:1]([O:28][CH:23]1[CH2:22][C:21]([CH3:30])([CH3:29])[N:20]([O:19][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[C:25]([CH3:26])([CH3:27])[CH2:24]1)=[O:11]
Reactant: [NH2-]
Reactant: COC(=O)/C=C/C=C/C(=O)OC
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)CC(OC(=O)/C=C/C=C/C(=O)OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1

Procedure:
A solution of 1.70 gram of dimethyl trans-transmuconate, 5.62 grams of 1-cyclohexyloxy-2,2,6,6-tetra-methylpiperidin-4-ol and 0.025 gram of lithium amide in 100 ml of toluene is heated under reflux with a Dean-Stark trap for 8 hours. The reaction mixture is then diluted with ethyl acetate, and then washed with water, brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure followed by chromatographic separation affords the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2([CH3:18])[C:14](OC)=[O:15])[C:5]([N+:19]([O-])=O)=[CH:4][N:3]=1.[H][H]>C1COCC1.C/C(/O)=C\C(C)=O.C/C(/O)=C\C(C)=O.O=[V]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:19][C:14](=[O:15])[C:9]3([CH3:18])[CH2:10][O:11][CH2:12][CH2:13][N:8]3[C:6]=2[N:7]=1
Reactant: [H][H]
Reactant: COC(=O)C1(C)COCCN1c1nc(Cl)ncc1[N+](=O)[O-]
Agent: O=[V]
Agent: CC(=O)/C=C(\C)O
Solvent: C1CCOC1
Product: CC12COCCN1c1nc(Cl)ncc1NC2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
Methyl 4-(2-chloro-5-nitropyrimidin-4-yl)-3-methylmorpholine-3-carboxylate (crude material, 8.4 g, about 20 mmol) and vanadyl acetylacetonate (0.7 g, 2.64 mmol) were mixed in THF (80 ml). The reaction mixture was hydrogenated under one atmosphere of hydrogen at 35° C. for 18 hours. The starting material was consumed. The reaction mixture was cooled to room temperature. MeOH (10 ml) was added to reaction mixture and stirred for 10 minutes. The mixture was filtered through a Celite® pad. The Celite® pad was washed with mixture of THF (60 ml) and MeOH (10 ml) twice and then a mixture of dichloromethane (80 ml) and methanol (20 ml) three times. The filtrate was combined with washes and concentrated to about 30 ml at which point a solid had precipitated out. EtOAc (40 ml) was added and the mixture was stirred for 10 minutes. The solid was collected by filtration, washed with EtOAc (50 ml) to afford 2.54 g of 2-chloro-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one. 1H NMR (400 MHz, CDCl3) δ=1.44 (s, 3H), 3.23 (m, 1H), 3.53 (m, 1H), 3.69 (d, 1H), 3.88-3.99 (m, 3H), 7.67 (s, 1H), 10.98 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].O1CCCC1.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O>[CH2:17]([CH:4]([C:5]#[N:6])[C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[Cl:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCBr
Reactant: N#CCc1ccc(Cl)cc1Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCC(C#N)c1ccc(Cl)cc1Cl
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Sodium hydride (0.13 moles as a 50% dispersion in mineral oil) is washed with 100 ml. of dry n-hexane to remove the mineral oil, then blanketed with dry nitrogen and suspended in 250 ml. of freshly distilled tetrahydrofuran. To this sodium hydride suspension is added dropwise at room temperature, a solution of 2,4-dichlorobenzyl cyanide (25g., 0.13 mole) dissolved in 100 ml. of tetrahydrofuran. When the addition is completed the temperature is maintained at 30° C. for an additional 0.5 hours. A solution of n-octylbromide (27g., 0.14 mole) is then added dropwise and the resultant reaction mixture is stirred at 40° C. overnight under nitrogen. The reaction mixture is poured into 1 liter of water and extracted with (3 × 200 ml.) of ether. The combined ether extracts are washed, with water, dilute hydrochloric acid, saturated sodium, bicarbonate solution saturated sodium chloride solution, and dried over magnesium sulfate. The solvent is evaporated to give 39.8g. (100%) of product.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH2:7][CH2:8][CH3:9])[C:4]([OH:6])=[O:5].[CH3:10]O>>[ClH:1].[CH3:10][O:5][C:4](=[O:6])[C@@H:3]([NH2:2])[CH2:7][CH2:8][CH3:9]
Reactant: CCC[C@H](N)C(=O)O
Reactant: CO
Agent: Cl
Product: CCC[C@H](N)C(=O)OC
Temperature: 0 °C
Yield: 85 %

Procedure:
Dry hydrochloric acid gas was bubbled through a mixture of (S)-2-amino-pentanoic acid (1.00 g, 8.53 mmol) in methanol cooled to 0° C. for 5 min. The vessel was sealed and the mixture heated to 50° C. overnight. The mixture was cooled, the solvent removed and the residue treated with methanol (repeated 3×). The residue was triturated with diethyl ether, dried under high vacuum to yield (S)-2-amino-pentanoic acid methyl ester hydrochloride (1.21 g, 85%) as a light yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (t, J=6.9 Hz, 3H), 1.12-1.51 (m, 2H), 1.76 (m, J=6.0 Hz, 2H), 3.74 (s, 3H), 3.98 (t, J=6.0 Hz, 1H), 8.59 (br. s., 3H).
Reaction SMILES: [Na].[CH2:2]([SH:4])[CH3:3].[CH2:5]([O:7][C:8]([C:10]1[C:11](Cl)=[N:12][CH:13]=[N:14][CH:15]=1)=[O:9])[CH3:6].CN(C=O)C.C1COCC1>O>[CH2:5]([O:7][C:8]([C:10]1[C:11]([S:4][CH2:2][CH3:3])=[N:12][CH:13]=[N:14][CH:15]=1)=[O:9])[CH3:6]
Reactant: CCS
Reactant: CCOC(=O)c1cncnc1Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cncnc1SCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
2.77 g of ethyl mercaptan sodium salt (80%) was added to a mixture of 4.69 g of 4-chloropyrimidine-5-carboxylic acid ethyl ester, 8 ml of DMF and 7 ml of THF was added under ice cooling, then the mixture was heated to room temperature, and stirred for 1 hour. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 2.41 g of 4-ethylsulfanylpyrimidine-5-carboxylic acid ethyl ester. 4-Ethylsulfanylpyrimidine-5-carboxylic acid ethyl ester
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:3]1=[O:30].[Cl:31]C(Cl)(Cl)C(Cl)(Cl)Cl.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>C(Cl)Cl.C1COCC1>[Cl:31][C:9]1[N:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[N:11]=[C:5]2[C:6]=1[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:30])[N:4]2[CH2:25][C:26]([CH3:27])([CH3:29])[CH3:28]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cn1c(=O)c2cn(Cc3ccc(-c4ccncc4)cc3)nc2n(CC(C)(C)C)c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1c(=O)c2c(Cl)n(Cc3ccc(-c4ccncc4)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
5-methyl-7-neopentyl-2-(4-(pyridin-4-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (500 mg, 1.24 mmol) and hexachloroethane (587 mg, 2.48 mmol) are dissolved in 8 mL of methylene chloride, and then 1.0 M LiHMDS (2.48 mL, 2.48 mmol) in THF is added dropwise. After the reaction mixture is stirred at room temperature for 10 min, 100 mL of deionized water is added, and then extracted with methylene chloride four times (30 mL×4). The combined organic phase is dried over anhydrous sodium sulfate. After filtration, the filtrate is evaporated to dryness to give 500 mg of crude product as brown solids, which is used in the next step without further purification. MS (ESI) m/z 438.2 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13](/[CH:15]=[CH:16]/[C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][C:13](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(C(C)C)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1ccc(-c2ccc(/C=C/C(=O)O)s2)cc1
Reaction time: 20 h
Yield: 89685.9 %

Procedure:
To a solution of methyl (E)-3-[5-(4-isopropylphenyl)-thiophen-2-yl]acrylate (0.75 mg) in THF/ethanol (10/10 ml) was added at room temperature 2N sodium hydroxide solution (2.0 ml), and the mixture was stirred for 20 hours. Under reduced pressure, the mixture was concentrated, and to the residue was added IN hydrochloric acid (10 ml). The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated. The resulting crystals were collected by filtration to give pale yellow crystals of (E)-3-[5-(4-isopropylphenyl)thiophen-2-yl]acrylic acid (639.7 mg).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=O)[CH2:8][O:9][CH2:10][C:4]=2[CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:13]=[N:12][C:5]2[NH:6][CH2:7][CH2:8][O:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1COCc2cc(Br)cnc2N1
Solvent: C1CCOC1
Product: Brc1cnc2c(c1)COCCN2
Temperature: 0 °C
Reaction time: 18 h
Yield: 38.1 %

Procedure:
To a solution of 3-Bromo-5,9-dihydro-6-oxa-1,9-diazabenzocyclohepten-8-one (1.0 g, 4.13 mmol) in THF (40 mL) at 0° C. was added BH3 (30 mL of a 1.0 M solution in THF, 30.0 mmol). The solution was heated to reflux. After 18 h, the solution was cooled to 0° C. and the reaction quenched with H2O (2.5 mL). The mixture was concentrated and the resulting off-white solid was dissolved in MeOH (30 mL) and NaOH (15 mL of a 2 N solution). The mixture was heated at reflux for 4 h. The MeOH was removed under reduced pressure. The resulting precipitate was collected by filtration and washed with H2O (20 mL). The white solid was dried to give the title compound (0.360 g, 38%). 1H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J=2.3 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 6.55 (br s, 1H), 4.47 (s, 2H), 3.74-3.70 (m, 2H), 3.16-3.12 (m, 2H); ESI MS m/z 229 (100%); 231(100%)[C8H9BrN2O+H]+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:23])[CH2:9][C:10]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1)=[O:11].[BH4-].[Na+].CCOC(C)=O>CCO>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH:10]([OH:11])[CH2:9][CH:8]([OH:23])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[CH:15][C:16]=1[O:21][CH3:22]
Reactant: CCCCCCC[C@H](O)CC(=O)CCc1ccc(O)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCCC(O)CC(O)CCc1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [8]-gingerol (0.1 g) in EtOH (15 mL) was added dropwise a solution of NaBH4 (0.02 g in 1 mL H2O). The mixture was stirred at room temperature for 3 hrs. After acidification, EtOAc was added and organic layer was washed with water twice. Evaporation of solvent left a white solid which was purified by gradient chromatography to afford the title compound as a colourless liquid in quantitative yield.
Reaction SMILES: CN(C)C=O.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[C:26](I)=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)=[CH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([Sn](CCCC)(CCCC)[C:40]1[S:41][CH:42]=[CH:43][N:44]=1)CCC>[Cu]=O.O>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[C:26]([C:40]4[S:41][CH:42]=[CH:43][N:44]=4)=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)=[CH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc2c(Oc3ccc(C)nc3I)ccnc2cc1OCc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: O=[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)nc3-c3nccs3)ccnc2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
N,N-Dimethylformamide (2 ml) was added to 7-benzyloxy-4-(2-iodo-6-methyl-pyridin-3-yloxy)-6-methoxyquinoline (100 mg), tetrakistriphenylphosphine palladium (23 mg), tri-n-butyl-(thiazol-2-yl)-tin (113 mg), and copper(II) oxide (32 mg) under an argon atmosphere, and the mixture was stirred at 100° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give the title compound (43 mg, yield 46%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([CH:20]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:21]N)=[CH:15][CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])[N:4]=[CH:3]1.[CH2:30]=O.[B-][C:33]#[N:34].[Na+].O>CO>[CH3:30][N:34]([CH3:33])[CH2:21][CH:20]([C:14]1[CH:13]=[C:12]2[C:17]([CH2:18][CH2:19][N:10]([S:7]([C:5]3[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=3)(=[O:9])=[O:8])[CH2:11]2)=[CH:16][CH:15]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [B-]C#N
Reactant: C=O
Reactant: Cn1cnc(S(=O)(=O)N2CCc3ccc(C(CN)Cc4ccccc4)cc3C2)c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)CC(Cc1ccccc1)c1ccc2c(c1)CN(S(=O)(=O)c1cn(C)cn1)CC2
Temperature: 25 °C
Yield: 18.1 %

Procedure:
0.058 mmol of 2-(2-(1-methyl-1H-imidazol-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-phenylpropan-1-amine (example 1) were dissolved in 2 ml of methanol. A solution of formaldehyde (0.351 mmol, 37%) and 0.351 mmol of sodium cyanotrihydroborate were added and the mixture was stirred at room temperature over night. H2O was added to the reaction mixture and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried over MgSO4 and filtered. The filtrate was concentrated to 6 mg of crude solid material. The solid was washed with diisopropyl ether and dissolved in methanol. An equimolar amount of 1 N HCl was added and the volatiles removed in vacuo. The residue was washed with diethyl ether, dissolved in H2O, acidified with 1 N HCl and washed with additional diethyl ether. The aqueous phase was freeze dried to give 4.6 mg of the desired product (16.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:28]([CH2:29][CH2:30][C:31](O)=[O:32])=[CH:27][O:26][N:25]=2)=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:28]2[C:24]([C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)=[N:25][O:26][CH:27]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: O=C(O)CCc1conc1-c1ccc(Cl)cc1
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2conc2-c2ccc(Cl)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (0.76 g), 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.66 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.49 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.41 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-diethylphosphonomethylphenyl)-3-[3-(4-chlorophenyl)-4-isoxazolyl]propionamide (1.14 g, yield 91%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 88–90° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:16]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH3:35])[N:28]=3)[N:15]2[CH3:42])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:44]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][N:15]([C:16](=[O:44])[CH2:17][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH3:42])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2[C:18](=[O:19])[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]([CH3:42])[C:16]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH3:35])[N:28]=2)=[CH:25][CH:24]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(Nc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)n2C)n1)c1ccccc1
Solvent: ClCCl
Product: CC(Nc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n(C3CCNCC3)n2C)n1)c1ccccc1
Product: CN(NC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a solution of 4-{4-(4-fluorophenyl)-2-methyl-5-oxo-3-[2-(1-phenylethylamino)-pyrimidin-4-yl]-2,5-dihydro-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester, 26, (9 g, 15.7 mmol) in CH2Cl2 (90 mL) is added 20% TFA in CH2Cl2. After stirring at room temperature for 0.5 h, the reaction mixture is concentrated in vacuo. Purification by preparatory HPLC affords 4.2 9 (45% yield) of the desired product: [α]D −41.0° (c 1.7, MeOH); 1H NMR (300 MHz, CD3OD) δ 8.25 (d, J=4.8 Hz, 1H), 7.40-7.00 (m, 9H), 6.40 (d, J=4.8 Hz, 1H), 5.11-5.05 (m, 1H), 4.51-4.41 (m, 1H), 3.61-3.55 (m, 2H), 3.33 (bd, J=1.5 Hz, 3H), 3.24-3.05 (m, 3H), 2.92-2.75 (m, 2H), 2.19-2.10 (m, 2H), 1.52 (d, J=6.9 Hz, 3H). HRMS calcd for C27H29FN6O (M+H)+473.2465; found 473.2460.