Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[N:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[N:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:8]1
Reactant: N=C(N)NN
Reactant: Cc1cnnc2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1cnnc2c1C(=NNC(=N)N)CC(c1cc(Cl)sc1Cl)C2
Yield: 190.1 %

Procedure:
To a mixture of 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.203 g) and aminoguanidine hydrochloride (80 mg) were added ethanol (6 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was refluxed for 1.5 hours and cooled. Precipitated crystals were filtered, washed with ethanol and dried to give 7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 131) (0.25 g) as crystals.
Reaction SMILES: C[N:2]1[CH2:7][CH:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[CH2:26]([O:25][C:23]([N:2]1[CH2:3][CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1=CCN(C)CC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=CCN(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 71.4 %

Procedure:
In 640 ml of benzene, 108.9 g of ethyl 1-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate and 41.6 g of diisopropylethylamine were dissolved, and subsequently, 279.1 g of ethyl chloroformate was added dropwise thereto over 70 minutes. The reaction mixture was heated under reflux for 30 minutes, followed by cooling the reaction mixture to room temperature. A saturated aqueous solution of sodium hydrogencarbonate was poured thereinto. After the reaction mixture was extracted with ethyl acetate, the extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:1) to yield 104.4 g of ethyl 1-ethoxycarbonyl-1,2,3,6-tetrahydropyridine-4-carboxylate as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]([C:10]1[CH:11]=[C:12]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:25])([F:24])[F:23])[NH:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCN(C(C)C)C(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:36])[CH:5]([C:10]1[CH:11]=[C:12]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:23])([F:24])[F:25])[N:17]2[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C(F)(F)F)N2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C(F)(F)F)N2Cc2ccccc2)c1
Temperature: 150 °C

Procedure:
4-Methyl-2-[4′-trifluoromethyl-5-(6-trifluoromethyl-piperidin-2-yl)-biphenyl-3-yl]-pentanoic acid ethyl ester, compound 7b (32 mg, 0.062 mmol), Benzyl bromide (55 μl, 0.46 mmol), DIEA (110 μl, 0.62), and tetrabutylammonium iodide (TBAI)(10 mg) in acetonitrile (0.5 mL) were combined and heated under microwave conditions 150° C. for 30 minutes. The reaction was diluted with EtOAc, washed with brine, sat. NaHCO3, and brine, dried over magnesium sulfate and filtered. Purification by silica gel chromatography gave the product as yellow oil. (56 mg, quant.) (M+H) 605.65, Found 606.2
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[N:13]=[C:14](F)[N:15]=[C:16]([NH:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1.FC(F)(F)C(O)=O>FC(F)(F)CO.C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[N:13]=[C:14]([NH:28][C:29]3[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=3)[N:15]=[C:16]([NH:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(Nc2nc(F)nc3c2ccn3Cc2ccccc2)c(C)c1
Reactant: N#Cc1ccc(N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: OCC(F)(F)F
Product: Cc1cc(C)c(Nc2nc(Nc3ccc(C#N)cc3)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 90 °C
Yield: 61.8 %

Procedure:
To a suspension of (7-benzyl-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-(2,4,6-trimethyl-phenyl)-amine (42 mg, 0.12 mmol) and 4-aminobenzonitrile (55 mg, 0.47 mmol) in 2,2,2-trifluoroethanol (4 mL) was added trifluoroacetic acid (0.072 mL, 0.94 mmol). The resulting solution was heated at 90° C. for 16 h, then cooled to room temperature. The reaction was concentrated to produce a brown oil and diluted with CH2Cl2 (30 mL). The organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 34 mg (64%) of 4-[7-benzyl-4-(2,4,6-trimethyl-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[C:11](Cl)(=[O:13])[CH3:12]>>[C:11]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[NH2:1])(=[O:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: Nc1c(Cl)cccc1CO
Product: CC(=O)OCc1cccc(Cl)c1N

Procedure:
This material was prepared from 2-amino-3-chlorobenzyl alcohol and acetyl chloride by the general procedure outlined in Example 98. The product was isolated as an amber oil and was characterized by IR and 'H NMR spectroscopy and combustion analysis.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[C:29]([OH:28])([CH3:34])[CH3:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CC(C)(O)C(=O)O
Agent: Cl
Product: CC(C)(O)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (92 mg, 88%), MS (ISP) m/z=417.5 [(M+H)+], mp 241° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 2-hydroxy-2-methyl-propionic acid.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Cl.[C:10]([NH:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[N:18][CH:17]=1)([CH3:13])([CH3:12])[CH3:11].CO.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[C:10]([NH:14][C:15](=[O:23])[C:16]1[C:21]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:9])=[CH:20][C:19]([CH3:22])=[N:18][CH:17]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1ccccc1[Mg]Cl
Reactant: Cc1ccc(C(=O)NC(C)(C)C)cn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2ccccc2C)c(C(=O)NC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 108.7 %

Procedure:
38.9 ml (38.9 mMol) o-Tolylmagnesium chloride solution (1M in THF) were added over 15 minutes to a solution of 2.5 g (10.1 mMol) N-tert.-butyl-6-methyl-nicotinamide in 12.5 ml THF cooled to 0° C. The suspension obtained was stirred overnight at room temperature, then one more hour at 50° C. After cooling to 0° C., 2.1 ml (51.9 mMol) methanol were added over 30 minutes (exothermic!), followed after 10 minutes by 3.5 g (15.6 mMol) 2,3-dichloro-5,6-dicyano-benzoquinone. After one hour at room temperature, the reaction mixture was concentrated under reduced pressure to a still stirrable oil, heated to 50° C. and 100 ml tert.-butyl-methylether were added. The suspension was stirred 30 minutes at reflux, 1 hour at room temperature and filtered. The filtrate was evaporated and the residue was purified by flash chromatography (50 g SiO2, eluent: AcOEt/n-heptane 2:1) to yield 3.1 g (84.5%) N-tert.-butyl-6-methyl-4-o-tolyl-nicotinamide as a light brown resinous solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:40]=[CH:39][C:25]([C:26]([NH:28][CH:29]5[CH2:32][N:31]([CH:33]6[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]6)[CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:41][CH3:42])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O.[CH:47]1([CH:50]=O)[CH2:49][CH2:48]1>CO>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:40]=[CH:39][C:25]([C:26]([NH:28][CH:29]5[CH2:30][N:31]([CH:33]6[CH2:38][CH2:37][N:36]([CH2:50][CH:47]7[CH2:49][CH2:48]7)[CH2:35][CH2:34]6)[CH2:32]5)=[O:27])=[CH:24][C:23]=4[O:41][CH3:42])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CC1
Reactant: COc1cc(C(=O)NC2CN(C3CCNCC3)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(C(=O)NC2CN(C3CCN(CC4CC4)CC3)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a solution of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(piperidin-4-yl)azetidin-3-yl)benzamide (13 mg, 0.023 mmol) in MeOH (2.5 mL) was added AcOH (0.03 mL), cyclopropane aldehyde (3 μL, 0.034 mmol), borane-pyridine complex (10 μL, 0.08 mmol), and left to stir overnight. The solvent was then removed and the product purified by reverse phase HPLC, free based, and lyophilized to yield a white solid (6.4 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm −0.03-0.14 (m, 3H) 0.34-0.51 (m, 2H) 0.80 (s, 1H) 1.17 (d, J=2.53 Hz, 2H) 1.60 (br. s., 6H) 1.71 (br. s., 2H) 1.94 (br. s., 5H) 2.13 (d, J=6.32 Hz, 2H) 2.82 (br. s., 2H) 2.96 (t, J=7.20 Hz, 2H) 3.52 (t, J=7.20 Hz, 2H) 3.92 (s, 1H) 4.05 (t, J=14.02 Hz, 2H) 4.38-4.50 (m, 1H) 4.70-4.82 (m, 1H) 7.41-7.58 (m, 2H) 7.98 (s, 1H) 8.22-8.33 (m, 2H) 8.61 (d, J=6.57 Hz, 1H). [M+H] calc'd for C33H44F2N8O3, 638. found 638.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@H:12]2[C:20]([OH:22])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.Cl>COCCOC.O>[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@H:12]2[C:20]([OH:22])=[O:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(I)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(O)[C@@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 2.15 g (4.66 mmol) of the 2,3-dihydro-1-[(4-iodophenyl)sulfonyl]-(2S)-1H-indole-2-carboxylic acid obtained according to Preparation IV(a) in 40 ml of DME is prepared and 13 ml of water are added, followed by 1.24 g (11.6 mmol) of sodium carbonate, 380 mg (0.46 mmol) of PdCl2dppf and 1.77 g (9.3 mmol) of 2-(trifluoromethyl)phenylboronic acid. The reaction medium is stirred at room temperature for 30 min and then at 90° C. for 30 min. After cooling, water is added and the medium is acidified with N hydrochloric acid. The mixture is then extracted with ethyl acetate. The organic phase obtained is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by reversed phase chromatography on RP18-grafted silica gel using an acetonitrile/water/trifluoroacetic acid mixture (8/2/0.02; v/v/v) as the eluent to give the product in the form of an orange oil (yield=80%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][O:12][CH2:13][CH2:14]I.CC(C)=O.C([O-])([O-])=O.[K+].[K+].COCCI>C1(C)C=CC=CC=1.CC(C)=O>[CH3:11][O:12][CH2:13][CH2:14][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: COCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: COCCOc1ccc2[nH]ccc2c1
Yield: 86.2 %

Procedure:
To a solution of 5-hydroxy-indole (15.2 g, 114 mmol) in 250 ml of dry acetone 2-methoxyethyl iodide (15 ml, 141 mmol, 1.25 equiv) and anhydrous K2CO3 (46.7 g, 338 mmol, 3 equiv) are added and the mixture is refluxed. Additional amounts of 0.5 equiv of 2-methoxyethyl iodide and K2CO3 are added each day. After 6 days TLC (toluene-acetone, 9:1) indicates the absence of starting material. The solid is removed by filtration, and the solvent is evaporated. The residue is taken up in dichloromethane (800 ml) and the solution is washed with 2 M aqueous HCl, 10% aqueous NaHCO3, and water. The organic layer is dried and concentrated. Column chromatography (toluene-acetone, 9:1) provides 5-(2-methoxyethoxy)-1H-indole (18.8 g, 86%). M.p. 58-60° C. (from ethyl acetate-light petroleum).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[C:7]1(=[O:12])[O:11][CH2:10][CH2:9][CH2:8]1>>[C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[OH:3][CH:8]([CH2:9][CH3:10])[C:7]([OH:11])=[O:12]
Reactant: C[C@H](O)C(=O)O
Reactant: O=C1CCCO1
Product: CC(O)C(=O)O
Product: CCC(O)C(=O)O
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 250.6 %

Procedure:
A 90% aqueous solution of L-lactic acid (32.4 g) and 3.75 g of γ-butyrolactone were put in a reaction vessel equipped with a stirrer and a nitrogen-introducing tube. After substitution of nitrogen gas was carried out three times, the temperature was raised by 10° C. per minute to 120° C. in a stream of nitrogen, and the mixture was concentrated at 120° C. for 5 hours with stirring. To the resulting concentrate was added 2.2 g of commercially available synthetic aluminum silicate containing 17% aluminum oxide. Then the temperature was raised to 200° C. and the pressure was reduced gradually to 20 mmHg over 30 minutes, followed by stirring at 220±15° C. for 3 hours. After the pressure was reduced gradually to 1 mmHg over 30 minutes, the mixture was stirred at 210±10° C. for 18 hours to give copolymer in the molten state. The product was cooled to room temperature to give 21.2 g of lactic acid-hydroxybutyric acid copolymer as a dark brown solid. The weight-average molecular weight of this copolymer was 65,000.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19][CH2:20]O>>[CH2:19]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[CH3:1])[CH3:20]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1C

Procedure:
2-Methyl-4-nitrobenzoic acid (10 g, 55.2 mmol) in EtOH (200 mL) was treated with sulfuric acid (2 mL) and stirred at reflux until the reaction was complete. The mixture was worked-up and purified to give the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH:14]([CH2:16][CH:17]1[CH:24]2[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:26][CH:18]1[CH2:19]3)[CH2:23]2)[CH3:15])(=[O:12])[CH:10]=[CH2:11].C(N(CC)CC)C.C(OCC)(=O)C>CO>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:11][CH2:10][C:9]([O:13][CH:14]([CH2:16][CH:17]2[CH:24]3[CH2:23][CH:22]4[CH2:21][CH:20]([CH2:19][CH:18]2[CH2:26]4)[CH2:25]3)[CH3:15])=[O:12])=[CH:3][CH:4]=1
Reactant: Oc1ccc(S)cc1
Reactant: C=CC(=O)OC(C)CC1C2CC3CC(C2)CC1C3
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(CC1C2CC3CC(C2)CC1C3)OC(=O)CCSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
4-Mercaptophenol (5.08 g) (40.3 mmol) and 10.0 g (40.3 mmol) of 2-adamantylpropan-2-yl acrylate were dissolved in 100 ml of MeOH. To the solution was added 4.08 g (40.3 mmol) of triethylamine and the solution was stirred at room temperature for 4 hours. Ethyl acetate (200 ml) was added to the solution, the organic layer was washed four times with saturated sodium hydrogencarbonate and two times with water in order, and the organic layer was dried with sodium sulfate. The solvent was concentrated to obtain 11.2 g (29.9 mmol) of 2-adamantylpropan-2-yl 3-(4-hydroxyphenylthio)propanoate as a white solid. A mixture comprising 3.0 g (8.0 mmol) of the solid, 2.53 g (8.0 mmol) of 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl difluoride, 1.22 g (8 mmol) of 7,11-diazabicyclo[5.4.0]undec-11-ene, and 100 ml of acetonitrile was stirred under nitrogen current at room temperature for 2 hours. Two hundred (200) ml of water and 200 ml of ethyl acetate were added to the solution, and the organic layer was washed with water, a saturated sodium chloride aqueous solution, and water in order, and the organic layer was dried with sodium sulfate. The solvent was concentrated, and the residue was dissolved in 50 ml of methanol and 50 ml of acetone. Sodium hydrogencarbonate (12.0 g) was added and the solution was stirred at 40° C. for 3 hours. Two hundred (200) ml of water and 200 ml of ethyl acetate was added thereto and the organic layer was washed with water, a saturated sodium chloride aqueous solution, and water in order, and the organic layer was dried with sodium sulfate. The solvent was concentrated to obtain brown oil. The oil was recrystallized with diisopropyl ether, and 3.08 g (4.46 mmol) of sodium 3-[4-{2-[(2-adamantylpropan-2-yloxy)carbonyl]ethylthio}-phenoxysulfonyl]-1,1,2,2,3,3-hexafluoropropane-1-sulfonate was obtained as a white solid. The white solid (1.80 g) (2.61 mmol) was dissolved in 100 ml of methanol, 0.895 g (2.61 mmol) of triphenylsulfonyl bromide was added thereto, and the solution was stirred at room temperature for 3 hours. Chloroform (200 ml) was added to the solution, the organic layer was washed with water, and the solvent was concentrated to obtain 2.63 g of a colorless transparent oily compound (A-79).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH2:22][C:23]([N:2]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[CH3:1])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: CNc1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)CCl)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material is prepared as follows: There are added to 30 g of 4-(N-methylamino)benzoic acid in 500 ml of dichloromethane 30.7 g of Hunig base and, at 5°, 24.6 g of chloroacetyl chloride in 50 ml of dichloromethane. After stirring for 2 hours at RT, the suspension is concentrated by evaporation, and the residue is digested with water, filtered with suction and washed with 1N hydrochloric acid. The mixture is digested with ether and filtered with suction, yielding 4-(N-chloroacetyl-N-methylamino)benzoic acid having a melting point (186°) of 195°-197°. 10 g thereof are boiled under reflux for 2 hours in 150 ml methylene chloride with 5 drops of pyridine with 15 ml of thionyl chloride, concentrated by evaporation and recrystallised from hexane. The resulting 4-(N-chloroacetyl-N-methylamino)benzoic acid chloride melts at 61°-63°.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C([Li])CCC.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].O>O1CCCC1>[CH:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][C:10]2[S:11][C:12]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Oc2nccs2)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(Oc2ccc(OC(C)C)cc2)s1
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of Example 1B (2.4 g, 0.01 mol) in dry tetrahydrofuran was added n-butyl lithium (4.4 mL, 2.5 M in hexane) at −78° C. drop wise. After stirring at this temperature for 1 h, tributyltin chloride (3.0 mL, 0.011 mol) was added slowly to the mixture. The brown solution was then stirred for 3 hours while warning up to room temperature. Water was added and the solution was extracted with ethyl acetate. The organic layer washed with saturated NH4Cl, brine, and then dried over magnesium sulfate. The solution was concentrated and the crude was purified on a silica gel flash column, eluting with 5-30% EtOAc in hexane, to give 4.85 g of the title compound (93% yield), 1H NMR (300 MHz, CDCl3) δ ppm 0.77-1.74 (m, 33 H) 4.40-4.63 (m, 1 H) 6.84-6.95 (m, 2 H) 7.12 (s, 1 H) 7.14-7.23 (m, 2 H). MS (ESI), m/z 526.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]1([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17]Br)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C1COCC1>[CH2:1]([NH:3][CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN
Reactant: BrCc1ccccc1Oc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCNCc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
Ethylamine (70% solution, 5.2 ml, 80 mmol) was diluted with water (5.2 ml). A solution of 2-bromomethylphenyl phenyl ether (5.0 g, 19.02 mmol) in THF (25 ml) was added dropwise and the reaction stirred at ambient temperature for 2 hours. The volatile components were removed at reduced pressure, aqueous sodium hydroxide (1N, 20 ml) was added and the aqueous solution extracted with dichloromethane (2×). The organic layers were dried (MgSO4), evaporated and purified by chromatography (eluant: CH2 Cl2 /EtOAc/MeOH) to give N-ethyl-N-(2-(phenoxy)benzyl)amine as a yellow solid (2.2 g, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(Cl)CCl.[CH:18]1[CH:19]=CC2N(O)N=[N:24][C:22]=2[CH:23]=1.CCN(CC)CC.Cl.[CH2:36]([O:43][C:44]([N:46]1[CH2:55][CH2:54][C:53]2[C:48](=[CH:49][C:50]([NH:56][C:57](=[O:69])[C:58]3[CH:63]=[CH:62][CH:61]=[C:60](C4CCCN4)[CH:59]=3)=[CH:51][CH:52]=2)[CH2:47]1)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[CH2:36]([O:43][C:44]([N:46]1[CH2:55][CH2:54][C:53]2[C:48](=[CH:49][C:50]([NH:56][C:57](=[O:69])[C:58]3([CH:19]4[CH2:18][CH2:23][CH2:22][N:24]4[C:6](=[O:8])[C:5]4[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:59]=[CH:60][CH:61]=[CH:62][CH2:63]3)=[CH:51][CH:52]=2)[CH2:47]1)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: On1nnc2ccccc21
Reactant: O=C(Nc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC2)c1cccc(C2CCCN2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCCC2C2(C(=O)Nc3ccc4c(c3)CN(C(=O)OCc3ccccc3)CC4)C=CC=CC2)cc1OC
Yield: 57.4 %

Procedure:
Stir a solution of 3,4-dimethoxybenzoic acid (85 mg, 0.461 mmol), EDC (91 mg, 0.461 mmol), HOBt (66 mg, 0.461 mmol), and Et3N (0.195 mL, 1.383 mmol) in DMF (7 mL) at room temperature for 30 min. To this add 7-(3-pyrrolidin-2-ylbenzoylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester HCl salt (236 mg, 0.384 mmol) as a solution in DMF and stir the reaction at room temperature for 48 h. Quench the reaction with sat. NH4Cl (100 mL) and extract with EtOAc (2×150 mL). Wash the organic layers with water (100 mL) then dry (Na2SO4) and concentrate to an oil. Purify by silica gel chromatography eluting with 10% EtOAc/hexane to 100% EtOAc. Concentrate the fractions containing product in vacuo to afford 137 mg of 7-{1-[1-(3,4-dimethoxy-benzoyl)-pyrrolidin-2-yl]-benzoylamino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester as a solid foam.