Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC1C=C2C(C(C=CC3C=CC=CC=3)=NN2COCC[Si](CC)(CC)CC)=CC=1.[CH3:30][N:31]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:32]1[CH:40]=[C:39]2[C:35]([C:36]([CH:49]=[CH:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[N:37][N:38]2COCC[Si](C)(C)C)=[CH:34][CH:33]=1.[K+].[Br-]>CCOC(C)=O.CCCCCC>[CH3:30][N:31]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:32]1[CH:40]=[C:39]2[C:35]([C:36]([CH:49]=[CH:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[N:37][NH:38]2)=[CH:34][CH:33]=1
Reactant: CN(c1ccccc1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Agent: CC[Si](CC)(CC)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(c1ccccc1)c1ccc2c(C=Cc3ccccc3)n[nH]c2c1

Procedure:
6-Iodo-3-styryl-1-[2-(triethyl-silanyl)-ethoxymethyl]-1H-indazole was converted to methyl-phenyl-{3-styryl-1 [2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-amine as described in Example 11, step (v). Rf sm 0.35 Rf p 0.13 (EtOAc:hexane 1:9); IR (KBr) 3031, 2951, 1625, 1595, 1498, 1449, 1326, 1303, 1248, 1212, 1076, 835, 694 cm−1; MS (ESI) [M+H]/z Calc'd 456, Found 456.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH:5]([CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[CH:12](=[O:15])[CH2:13][CH3:14]>N1CCCCC1.C(O)(=O)C>[CH3:14][C:13](=[CH:10][CH2:9][CH:5]1[CH2:4][CH:3]=[C:2]([CH3:1])[C:6]1([CH3:7])[CH3:8])[CH:12]=[O:15]
Reactant: CCC=O
Reactant: CC1=CCC(CC=O)C1(C)C
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(C=O)=CCC1CC=C(C)C1(C)C
Temperature: 100 °C
Yield: 80.6 %

Procedure:
A 500 mL four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel was charged with 171 g (0.98 mol) of campholenic aldehyde (purity: 88%), 3.8 g (0.045 mol) of piperidine and 2.8 g (0.046 mol) of acetic acid, and the contents in the flask were stirred while heating at 100° C. Then, 92 g (1.6 mol) of propionaldehyde was gradually dropped into the flask for 6 h, and the resultant mixture was aged for 1 h and then cooled. Thereafter, 3.2 g (0.053 mol) of acetic acid was added to the mixture to remove amines therefrom, thereby separating the mixture into two layers. The thus separated organic layer was washed with water and separated into two layers, thereby obtaining 279 g (0.79 mol) of 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-but-2-en-1-al (purity as measured by gas chromatography: 54.7%) (yield based on theoretical amount: 81%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[CH:17]1([CH2:22][CH2:23]CS([O-])(=O)=O)[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[O:10][CH2:23][CH2:22][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Oc1c(I)cc(I)cc1I
Reactant: O=S(=O)([O-])CCCC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1cc(I)c(OCCC2CCCC2)c(I)c1
Temperature: 65 °C
Yield: 72.2 %

Procedure:
To a stirred mixture of 2,4,6-triiodophenol (20.36 g, 43.2 mmol) and milled anhydrous potassium carbonate (7.2 g, 52.2 mmol) in 75 ml of dry dimethylformamide was added dropwise over 10 minutes, a solution of 2-cyclopentylethylmethanesulfonate (8.2 g, 42.7 mmol) in 10 ml of dimethylformamide. The mixture was heated at 65° C. under argon overnight and the solvent was then removed under vacuum. The resulting amber residue was partitioned between ethyl acetate (200 ml) and water (30 ml). The aqueous layer was further extracted with ethyl acetate (2×250 ml) and the combined ethyl acetate extracts were treated with decolorizing carbon, dried over magnesium sulfate and passed through a short pad of basic alumina. The filtrate was evaporated under vacuum to give 17.5 g (73%) of the desired product as an amber oil.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6](=[O:21])[CH2:7][C:8]([NH:10][C:11]1[C:12]([C:17]([O:19]C)=O)=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:9].O>C1COCC1>[OH:19][C:17]1[C:12]2[C:11](=[CH:16][CH:15]=[CH:14][N:13]=2)[NH:10][C:8](=[O:9])[C:7]=1[C:6]([O:5][CH3:4])=[O:21]
Reactant: COC(=O)CC(=O)Nc1cccnc1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(O)c2ncccc2[nH]c1=O
Reaction time: 8 h

Procedure:
Sodium methoxide (0.73 g, 13.5 mmol) was added to 2 methyl 3-[(3-methoxy-3-oxopropanoyl)amino]pyridine-2-carboxylate (0.9 g, 3.4 mmol) dissolved in THF (20 mL). The reaction was stirred overnight. Water was added and the solvents removed. The residue was dissolved in water and purified by reverse phase HPLC eluting with a gradient of 5-40% acetonitrile/water (0.1% TFA) to give the product as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]([O:9][C:10]2[CH:11]=[C:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C:13]([NH:16][C:17]([NH2:19])=[S:18])=[N:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[CH2:28][CH:29]=O>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]([O:9][C:10]2[CH:11]=[C:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C:13]([NH:16][C:17]3[S:18][CH:28]=[CH:29][N:19]=3)=[N:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: O=CCCl
Reactant: COCCOc1cc(Oc2ccc(S(C)(=O)=O)cc2)cnc1NC(N)=S
Solvent: CN(C)C=O
Product: COCCOc1cc(Oc2ccc(S(C)(=O)=O)cc2)cnc1Nc1nccs1
Temperature: 100 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
[5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-pyridine-2-yl]-thiourea (0.28 mmol) is dissolved in DMF (1 ml) and chloro-acetaldehyde (1.1 eq., 55% in water) is added and stirred three hours at 100° C. After cooling to room temperature the suspension is pored into ice-water and extracted with methyl-tert.-butyl ether. The combined organic phases are washed with brine and dried over MgSO4. The solvent is removed in vacuo. [5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-pyridine-2-yl]-thiazole-2-yl-amine (“A32”) is obtained after reversed phase column chromatography (acetonitrile/water+0.1% TFA) as yellow solid in a yield of 22%. HPLC (method C): 1.52 min; LC-MS (method A): 1.37 min, 422.15 (MH+); 1H-NMR (DMSO-d5, 500 MHz): δ [ppm] 10.272 (s, 1H), 7.906 (d, 2H, J=8.8 Hz), 7.853 (d, 1H, J=2.3 Hz), 7.462 (d, 1H, J=3.7 Hz), 7.44 (d, 1H, J=2.3 Hz), 7.201 (d, 2H, J=8.8 Hz), 7.087 (d, 1H, J=3.7 Hz), 4.261 (t, 2H, J=4.5 Hz), 3.764 (t, 2H, J=4.5 Hz), 3.333 (s, 3H), 3.184 (s, 3H).
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([N:23]([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)C=CC=CC=1.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1>O1CCOCC1>[CH3:24][N:23]([CH3:25])[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:8]([N:40]2[CH2:39][CH:38]=[C:37]([C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([Cl:27])[CH:29]=4)[NH:33][CH:32]=3)[CH2:42][CH2:41]2)=[O:7])[CH2:12][CH2:13]1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)N2CC=C(c3c[nH]c4ccc(Cl)cc34)CC2)CC1
Yield: 8.7 %

Procedure:
The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (705 mg, 2 mmole) was added to a solution of 5-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (465.4 mg, 2 mmole) in dioxane (12 ml). The reaction mixture was then boiled under reflux for 20 hours. The reaction mixture was a suspension at RT. The solid was filtered off, washed with cold dioxane (3×2 ml) and dried. The solid was the polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (259 mg, m.p. 120°-130° C., 26%). The reaction solution (filtrate and wash phases) was concentrated by evaporation and water (10 ml) was added to the residue. The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The combined EE extracts were washed with 1M NaOH (1×5 ml) and dried with Na2SO4. The solvent was distilled off in vacuo. The residue contained phenol and mainly the non-polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (80 g). Ethanol (1000 ml) was used as eluent. The non-polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (304 mg, m.p. 216°-222° C., 31%) and a further part of the polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (85 mg, m.p. 108°-111° C., 9%) were thereby isolated.
Reaction SMILES: [C:1]1(S(N)(=O)=O)C=CC=CC=1.[CH2:11]([NH2:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CC[O-].[Na+].S(=O)(=O)(O)O.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][NH:19][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CCCCCCCCN
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCCCCCCCNC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
523 g of benzene sulfonamide of octylamine are dissolved in 1500 cc of anhydrous xylene. There are then introduced, with agitation, 835 cc of a 2.4N ethanolic solution of sodium ethylate. The ethanol is then eliminated by distillation. While agitating the reaction mixture and maintaining its temperature at 100°-110° C., there are introduced over a one hour period 385 cc of methyl sulfate. The resulting mixture is heated at reflux for 4 hours. After cooling, the mineral salts formed are removed by filtration. There are then added to the filtrate 1500 cc of a concentrated aqueous solution of NaOH. The resulting mixture is decanted and the xylenic phase is washed 4 times with 1000 cc of water and then concentrated. The residue obtained is added to a mixture of 1400 g of concentrated sulfuric acid and about 560 g of crushed ice. The resulting mixture is then brought, with agitation, to 160° C. for 16 hours. After cooling, the reaction mixture is poured onto 3 kg of crushed ice and made alkaline by the addition of 3500 cc of a concentrated aqueous solution of NaOH, which is then extracted three times with 2000 cc of ethyl acetate. The organic phase is then washed with water, dried and concentrated under reduced pressure. The residue is distilled and the fraction distilling at 45°-50° C. under 0.2 mm Hg is recovered.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=1
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CN1CCCCC1)C2

Procedure:
The title compound was prepared (0.095 g, 72%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and piperidine (0.58 g, 6.76 mmol). mp >235° C.
Reaction SMILES: C[Mg]Cl.[C:4]([O:8][C:9](=[O:24])[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[N:17]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]1)([CH3:7])([CH3:6])[CH3:5].[CH2:25]([SiH](CC)CC)C.FC(F)(F)C(O)=O>O1CCCC1>[C:4]([O:8][C:9](=[O:24])[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[N:17]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:25])=[CH:18]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1n1ccc(C=O)c1
Reactant: CC[SiH](CC)CC
Agent: C[Mg]Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCc1ccn([C@@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)c1
Reaction time: 3 h
Yield: 27.2 %

Procedure:
Methylmagnesium chloride solution (3 M in tetrahydrofuran, 0.23 ml, 0.68 mmol) was added at −78° C. to a solution of trans-[2-(3-formyl-pyrrol-1-yl)-cyclohexyl]-carbamic acid tert-butyl ester (example 26a, 100 mg, 0.34 mmol) in tetrahydrofuran (2 ml), then after 3.5 h the reaction was quenched by addition of saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic layer was washed with brine, dried (MgSO4), and evaporated. This crude material (103 mg) was dissolved in dichloromethane (2 ml) and treated with triethylsilane (58 mg, 0.50 mmol) and trifluoroacetic acid (190 mg, 1.67 mmol). The reaction mixture was allowed to reach 0° C. over 3 h, then evaporated and the residue chromatographed (SiO2, heptane-ethyl acetate gradient) to afford the title compound (27 mg, 28%). Yellow solid, MS (ISP) 293.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:16][CH2:15][O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:17][CH:18]1CCOC(=O)CCCCCCCOCC1>>[CH3:1][CH:2]1[CH2:16][CH2:15][O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:18][CH2:17][O:5][CH2:4][CH2:3]1
Reactant: CC1CCOCCCCCCC(=O)OCC1
Reactant: CC1CCOCCCCCCCC(=O)OCC1
Product: CC1CCOCCCCCCCCC(=O)OCC1

Procedure:
Odor: Musk, animalic, warm-powdery, flowery, slightly after saffron.--IR (film): n=1734 cm-1 (νC=O), 1118/1151 cm-1 (νasO--C--C), 1250 cm-1 (νasC--C(=O)--O), 1357 cm-1 (δCH3), 1061 cm-1 (νasC--O--C).--1H-NMR (CDCl3): δ=0.91 (d, J=6.4 Hz, 3H, 13-Me), 1.31-1.66 (m, 15H, 3-H2 -8-H2, 12-H2, 14-Hb), 1.83 (ddt, J=19.1, 9.6 and 5.0 Hz, 1H, 14-Ha), 1.93 (mc, 1H, 13-H), 2.33 (dd, J=6.9 and 6.2 Hz, 2H, 2-H2), 3.34-3.52 (m, 4H, 9-,11-H2), 4.14 (ddd, J=11.0, 5.5 and 5.0 Hz, 1H, 15-Hb), 4.21 (ddd, J=11.0, 10.0 and 4.0 Hz, 1H, 15-Ha).--13C-NMR (CDCl3): δ=18.22 (q, 13-Me), 24.67/25.26 (t, C-3,-7), 25.53 (d, C-13), 27.21/27.40/27.52 (t, C-4,-5,-6), 28.68 (t, C-8), 34.67 (t, C-2), 35.49 (t, C-14), 37.01 (t, C-12), 61.74 (t, C-15), 67.67/70.16 (t, C-9,-11), 173.93 (s, C-1).--MS (El): m/z (%)=55 (100) [C4H7⊕ ], 83 (64) [C6H11⊕ ], 99 (30) [C6H11O⊕ ], 138 (25) [M⊕ --C6H14O2 ], 155 (23) [M⊕ --C6H13O], 213 (2) [M⊕--C2H3O], 227 (2) [M⊕ --CHO], 256 (1) [M⊕ ].--C15H28O3 (256,39): calculated C 70.27, H 11.01; found C 70.26, H 11.09.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21](C(OCC)C)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1COCC1.[OH-].[Na+]>Cl>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(C)n1cc(-c2ncnc3c2ccn3COC(=O)C(C)(C)C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
To a solution of crude {4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (4) in THF (1 L, 12.3 mol), a 4 N aqueous HCl solution (500 mL) was added at room temperature. The resulting reaction mixture was subsequently stirred at room temperature for 5 h. When the reaction was deemed complete as confirmed by TLC and LCMS, the reaction mixture was cooled to 0-5° C. before pH was adjusted to 9-10 with a 1 M aqueous sodium hydroxide (NaOH) solution (2 L). The mixture was concentrated under reduced pressure to remove most of THF and the resulting suspension was stirred at room temperature for 2 h. The solids were collected by filtration, washed with water (3×500 mL), and dried in vacuum to afford crude [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (5, 157.5 g, 204.43 g theoretical, 77% yield for three steps) as white to off-white solids, which was found to be sufficiently pure (>98area % by HPLC) to do the subsequent reaction without further purification. For 5: 1H NMR (DMSO-d6, 400 MHz) δ ppm 13.42 (br s, 1H), 8.76 (s, 1H), 8.67 (s, 1H), 8.33 (s, 1H), 7.68 (d, 1H, J=3.8 Hz), 7.11 (d, 1H, J=3.8 Hz), 6.21 (s, 2H), 1.06 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 177.74, 152.31, 152.09, 151.91, 139.52, 130.39, 120.51, 113.93, 101.91, 67.26, 38.98, 27.26; C15H17N5O2 (MW, 299.33), LCMS (EI) m/e 300 (M++H).
Reaction SMILES: [Cl:1][C:2]([Cl:21])([Cl:20])[CH2:3][O:4][C:5](=[O:19])[CH:6]([O:16][CH2:17][CH3:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.[O-:22][Mn](=O)(=O)=O.[K+].[O-]S([O-])=O.[Na+].[Na+]>CC(C)=O.CCOC(C)=O.Cl>[CH2:17]([O:16][CH:6]([C:5]([O:4][CH2:3][C:2]([Cl:20])([Cl:21])[Cl:1])=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:22])=[O:15])=[CH:10][CH:9]=1)[CH3:18]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCOC(Cc1ccc(CO)cc1)C(=O)OCC(Cl)(Cl)Cl
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(Cc1ccc(C(=O)O)cc1)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Ethoxy-3-(4-hydroxymethyl-phenyl)-propionic acid 2,2,2-trichloroethyl ester (0.044 g, 0.125 mmol) was dissolved in acetone (3 mL) and KMnO4 (0.039 g, 0.247 mmol) was added and the purple solution was stirred for 4 h at room temperature. Saturated aq. Na2SO3 solution was added and after 2 min. stirring, the mixture was diluted with EtOAc and aq. HCl (2N) resulting in two clear and colorless phases. The organic layer was separated and dried (MgSO4) and evaporated to afford the desired carboxylic acid which was proceeded on to the next step without further purification (0.034 g, 75%). 1H NMR (400 MHz, CDCl3): δ 8.01-8.03 (d, 2H), 7.36-7.38 (d, 2H), 4.73-4.83 (q, 2H), 4.15-4.18 (m, 1H), 3.65-3.69 (m, 1H), 3.33-3.37 (m, 1H), 3-07-3.20 (m, 2H), 1.14 (t, 3H).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[NH2:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH2:13][S:14][CH3:15].C(=O)([O-])[O-].[Na+].[Na+].[BH4-].[Na+]>O>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH2:1][NH:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH2:13][S:14][CH3:15]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: Nc1ccccc1C=O
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CSCC[C@H](NCc1ccccc1N)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 0.1 mol of anthranil aldehyde, 0.1 mol of methionine and a solution of 0.1 mol of sodium carbonate in 50 ml of water was stirred for a few hours. After everything had gone into solution, 0.1 mol of sodium borohydride was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was then acidified to pH3, and the precipitate was collected and dried, yielding 85% of theory of N-(2-amino-benzyl)-methionine, m.p. 198° C. The total yield, based on the anthranilic acid starting material, was 68% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].FC(F)(F)S(O[C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[CH:27][CH:26]=[CH:25]2)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.C1(C)C=CC=CC=1>[N:28]1[C:29]2[C:24](=[CH:23][CH:22]=[CH:21][C:20]=2[C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[O:4])[CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: O=S(=O)(Oc1cccc2cccnc12)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cccc(-c2cccc3cccnc23)c1
Yield: 84.9 %

Procedure:
1.04 g (5.77 mmol) of m-(methoxycarbonyl)phenyl boronic acid, 1.00 g (3.67 mmol) of quinolin-8-yl trifluoro-methanesulfonate, 125 mg (0.11 mmol) of tetrakis(triphenylphosphine)palladium(0), and 611 mg (5.77 mmol) of sodium carbonate were heated under reflux in a mixed solvent comprising 4 mL of H2O, 23 mL of toluene, and 6.7 mL of methanol for 20 hours. After the completion of the reaction, the organic solvent was distilled off under reduced pressure, H2O was added to the residue, and ethyl acetate extraction was performed. Subsequently, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography, thereby giving 820 mg of methyl 3-(quinolin-8-yl)benzoate (yield: 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.I[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2=O
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CCN(c1cnccc1C)C2=O
Yield: 53.1 %

Procedure:
Using analogous reaction conditions as described in Example 1, 6-methoxy-3,4-dihydro-2H-isoquinolin-1-one (I-11d: 0.400 g, 2.2471 mmol) was reacted with 3-iodo-4-methyl-pyridine (0.492 g, 2.2471 mmol), 1,4-dioxane (40 mL), copper iodide (0.042 g, 0.2247 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.095 g, 0.6741 mmol) and potassium phosphate (1.190 g, 5.6177 mmol) to afford the crude product. Purification by column chromatography on silica gel (80% ethylacetate in hexane) afforded 0.320 g of the product (53% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][N:17]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)[N:16]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:30][CH:31]=2)[N:16]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1nn(Cc2ccc(Oc3ccccc3)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
After a mixture of ethyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (1600 mg), 1N sodium hydroxide solution (5 ml), tetrahydrofuran (10 ml), and ethanol (10 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (5 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylic acid (1470 mg, yield: 97%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 222–223° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH:9]=2)=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C.[Pt]=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2=CC3CCC(C2)N3)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: Fc1ccc(C2CC3CCC(C2)N3)cc1
Yield: 89.1 %

Procedure:
A solution of 3-(4-fluorophenyl)-8-azabicyclo[3,2,1]oct-2-ene (10 g) was dissolved in glacial acetic acid (150 ml). Platinum oxide (0.5 g) was added followed by treatment with hydrogen gas at 3 atm of pressure in a conventional Parr apparatus. Filtration and removal of solvent in vacuo left a viscous oil. Water was added and the mixture made alkaline (pH >9) with aqeous NaOH. Extraction with ethyl acetate, drying of the organic phase over magnesium sulfate and removal of solvent in vacuo gave 3-(4-fluorophenyl)-8-azabicyclo[3,2,1]-octane (9 g) as an oil.