Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCBr.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15](I)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[Cl:19][C:20]1[N:28]=[C:27]2[C:23]([N:24]=[C:25](I)[N:26]2[CH3:29])=[C:22]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:21]=1.C(Cl)Cl>CC(N(C)C)=O.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:25]2[N:26]([CH3:29])[C:27]3[C:23]([N:24]=2)=[C:22]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:21]=[C:20]([Cl:19])[N:28]=3)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: Cn1c(I)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: BrCCBr
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: Cn1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
To a suspension of zinc powder (320 mg, 4.92 mmol) and Celpure P65 in anhydrous DMA (3 mL) was added a 7:5 (v:v) mixture of TMS-C1:1,2-dibromoethane (65 μL) drop wise. The reaction mixture was stirred at room temperature for 15 min. A solution of 4-iodopiperidine-1-carboxylic acid tert-butyl ester (1.22 g, 3.95 mmol) in anhydrous DMA (2 mL) was added dropwise to the mixture described above and the reaction mixture was stirred for 30 minutes at room temperature. The zincate mixture was quickly filtered through a grade-3 sintered funnel and added onto a mixture of 2-Chloro-8-iodo-9-methyl-6-morpholin-4-yl-9H-purine (1.0 g, 2.63 mmol), Pd(dppf)Cl2.DCM (107 mg, 0.13 mmol) and CuI (50 mg, 0.26 mmol). The vessel was then evacuated and back-filled with nitrogen. The resulting reaction mixture was stirred at 85° C. for 18 hours, after 3 hours additional Pd(dppf)Cl2.DCM and CuI was added. The mixture was cooled to room temperature and partitioned between EtOAc and sat. aqueous solution of ammonium chloride. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (cyclohexane:EtOAc, 20-70%) affording 4-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-piperidine-1-carboxylic acid tert-butyl ester as a solid (375 mg, 33%). LCMS (Method H): RT 4.57 min, [M+H]+ 437.46 1H NMR (400 MHz, CDCl3): δ 4.40-4.15 (m, 6 H); 3.81 (t, J=12.1 Hz, 4 H); 3.71 (s, 3); 2.99-2.87 (m, 3 H); 1.94-1.85 (m, 4 H); 1.71-1.59 (m, 1 H); 1.48 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]([N:13]3[CH:17]=[N:16][CH:15]=[N:14]3)[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:18]1([CH2:10][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([OH:9])[CH:11]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH3:12])[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: CC(n1cncn1)C1(c2ccc(F)cc2)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(n1cncn1)C(O)(Cn1cncn1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 49.1 %

Procedure:
To a solution of 2-(4-fluorophenyl)-2-[1-(1H-1,2,4-triazol-1-yl)ethyl]oxirane (0.5 g, 2.1 mMole) in dimethylformamide (30 ml) was added 1,2,4-triazole (0.29 g, 4.2 mMole) and anhydrous potassium carbonate (0.29 g, 2.1 mMole). Heating, with stirring, was carried out for three hours at 85°. The solvent was evaporated, water (65 ml) was added, and the mixture was then extracted with methylene chloride (3×20 ml). The combined organic extracts were washed with water (3×10 ml), dried over anhydrous magnesium sulphate and evaporated to a gum, (1.1 g). Purification of the gum was carried out using a flash column of Merck "Kieselgel 60" (Trademark) 230-400 mesh silica eluting with methylene chloride containing gradually increasing amounts of methanol (from 5 to 10%). The appropriate fractions, on evaporation, gave the title compound, 318 mg; m.p. 103°-106° (49.1% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([C:15]([CH2:19][CH3:20])(O)[CH2:16][CH3:17])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[C:21]1([CH3:28])[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][CH:22]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([C:15]([CH2:16][CH3:17])([C:23]3[CH:24]=[CH:25][C:26]([OH:27])=[C:21]([CH3:28])[CH:22]=3)[CH2:19][CH3:20])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: Cc1ccccc1O
Reactant: CCOC(=O)c1cc2ccc(C(O)(CC)CC)cc2s1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1cc2ccc(C(CC)(CC)c3ccc(O)c(C)c3)cc2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a mixture of 6-(1-ethyl-1-hydroxy-propyl)-benzo[b]thiophene-2-carboxylic acid ethyl ester (0.650 g, 2.23 mmol and o-cresol (0.480 g, 4.45 mmol) in CH2Cl2 (20 mL) at −78° C. is added BF3-Et2O (0.316 g, 2.23 mol). After stirring for 10 min, the reaction mixture is allowed to warm to 0° C. over 30 min. The reaction is quenched with water (15 mL) and extracted with EtOAc (2×50 mL). The organic layer is dried over Na2SO4, concentrated, and purified by silica gel column chromatography to give the title compound (0.780 g, 92%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](O)=[O:7].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[N:20]1([N:25]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[CH:24]=[CH:23][CH:22]=[CH:21]1>C(Cl)Cl.O>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:21]1[N:20]([N:25]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[CH:24]=[CH:23][CH:22]=1)=[O:7]
Reactant: O=C(O)c1ccc[nH]1
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc[nH]1)c1cccn1N1C(=O)c2ccccc2C1=O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
To a suspension of pyrrole-2-carboxylic acid (5.55 g) in 500 ml of DCM was added oxalyl chloride (8.7). The reaction mixture was heated under reflux for 1 hour, cooled to -10° C., and tin (IV) chloride (5.85 ml) was added. After stirring the mixture at -10° C. for 30 minutes, 2-(1H-pyrrol-1-yl)-1H-isoindole-1,3(2H)dione (10.6 g) was added in four portions over a period of 30 minutes, followed by stirring at -10° C. for additional 30 minutes. The reaction mixture was then poured into 500 ml of water and extracted with DCM. The combined extracts were washed with 1N sodium hydroxide solution, 1N sulfuric acid, and finally with water. The dried (magnesium sulfate) organic phase was filtered and evaporated in vacuo. The residue was triturated with DCM, affording the product as a powder (10.55 g), mp 204°-206° C.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(C)([O-])C.[K+].[C:33]([O:37][C:38]([N:40]1[CH2:44][C:43](=O)[CH2:42][C@@H:41]1[C@H:46]1[O:50][C:49]([CH3:52])([CH3:51])[N:48]([C:53](=[O:55])[CH3:54])[C@H:47]1[CH2:56][C:57]1[CH:62]=[C:61]([F:63])[CH:60]=[C:59]([F:64])[CH:58]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>C1COCC1>[C:33]([O:37][C:38]([N:40]1[CH2:44]/[C:43](=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])/[CH2:42][C@@H:41]1[C@H:46]1[O:50][C:49]([CH3:51])([CH3:52])[N:48]([C:53](=[O:55])[CH3:54])[C@H:47]1[CH2:56][C:57]1[CH:58]=[C:59]([F:64])[CH:60]=[C:61]([F:63])[CH:62]=1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC(=O)CN2C(=O)OC(C)(C)C)OC1(C)C
Reactant: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCC/C=C1/C[C@H]([C@H]2OC(C)(C)N(C(C)=O)[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 76.8 %

Procedure:
Place under argon a suspension of n-hexyltriphenylphosphonium bromide (0.420 g, 1 mmol) in 10 mL of dry THF. Add potassium tert-butoxide (0.112 g, 1 mmol). Stir the mixture for 1 h. Add a solution of (R)-2-[(4S,5S)-3-Acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (0.045 g, 0.1 mmol) in 5 mL of dry THF. Stir the mixture overnight. Add water, extract with diethyl ether, dry over MgSO4, concentrate under reduced pressure and purify (silica gel chromatography, eluting with ethyl ether:hexane mixtures) to give the title compound (0.04 g, 76%).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.CS([Cl:27])(=O)=O.O>C(Cl)Cl>[Cl:27][CH2:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([S:2][CH3:1])[S:4][C:5]=2[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CSc1nc2ccc(CO)cc2s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CSc1nc2ccc(CCl)cc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a stirred mixture of (2-(methylthio)benzo[d]thiazol-6-yl)methanol (1.05 g, 5 mmol) from Step 3 of this Example and DIEA (1.3 mL, 7.5 mmol) in anhydrous CH2Cl2 (20 mL) under argon at −10° C. was added dropwise a solution of methanesulfonyl chloride (0.6 g, 5.5 mmol) in CH2Cl2 (10 mL). The mixture was allowed to warm to rt and stirred for 3 h. Additional methanesulfonyl chloride (190 mg, 1.7 mmol) was added, and the mixture was stirred for a further 2 h. Water (50 mL) was added, and the mixture was stirred for 10 min. The resulting mixture was then extracted with CH2Cl2 (200 mL). The CH2Cl2 layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (1.0 g, 88%) as a light red solid. The material was used in the next step without further purification. LCMS (ESI) m/z 230 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[NH:19]1[C:27]2[C:22](=[C:23]([CH2:28][NH2:29])[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1>>[NH:19]1[C:27]2[C:22](=[C:23]([CH2:28][NH:29][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:13]=[C:12]([O:14][CH2:15][CH:16]5[CH2:18][CH2:17]5)[NH:11][N:10]=4)[CH:5]=[CH:4][N:3]=3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: Clc1nccc(Nc2cc(OCC3CC3)[nH]n2)n1
Reactant: NCc1cccc2[nH]ccc12
Product: c1cc(CNc2nccc(Nc3cc(OCC4CC4)[nH]n3)n2)c2cc[nH]c2c1

Procedure:
N2-((1H-indol-4-yl)methyl)-N4(5-(cyclopropylmethoxy)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (I-42) was prepared analogously except 77 was replaced with (2-chloro-pyrimidin-4-yl)-(5-cyclopropylmethoxy-1H-pyrazol-3-yl)-amine and (1H-indol-4-yl)methanamine was replaced with 116.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:9]1[N:10]=[C:11]([NH2:13])[S:12][C:8]=1[CH2:7][CH2:6]2.N1C=CC=CC=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ClCCl>ClC(Cl)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:9]1[N:10]=[C:11]([NH:13][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:12][C:8]=1[CH2:7][CH2:6]2
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2c(c1)CCc1sc(N)nc1-2
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1nc2c(s1)CCc1cc(O)ccc1-2)c1ccccc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 14.9 %

Procedure:
To 7-methoxy-4,5-dihydronaphtho[1,2-d]thiazol-2-amine (17 mg, 0.073 mmol) in dichloroethane (2 mL) and pyridine (17.37 mg, 0.220 mmol) was added benzoyl chloride (0.015 mL, 0.132 mmol) at room temperature. The reaction mixture was heated to 45° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature, 3 ml of dichloromethane was added, and the contents were washed with sat. NaHCO3. The organic layer was dried over Na2SO4 and concentrated and dried under vacuum overnight. The residue was dissolved into 2 ml dichloromethane, cooled to 0° C. using an ice bath. Borontribromide (0.293 mL, 0.293 mmol) was added slowly at 0° C. The reaction mixture was allowed to warm to room temperature slowly and stirred at room temperature for 4 hours. The reaction mixture was quenched with a few drops of MeOH and purified on prep. HPLC (Luna 5 u C18 21.2*100 mm column; 0%-100% 10mins gradient; Solvent A: 10% MeOH-90% H2O-0.1% TFA; Solvent B: 90% MeOH-90% H2O-0.1% TFA). The desired fractions were collected, concentrated and dried overnight to provide 3.5 mg of product. (two-step yield: 11%). LC/MS M+1=323.1. The product had an HPLC retention time=3.31 min. (condition A). 1H NMR (400 MHz, CD3OD) δ ppm 7.99-8.07 (2H, m), 7.63 (2H, d, J=7.48 Hz), 7.57 (2H, d, J=7.70 Hz), 6.70 (2H, s), 2.98 (4H, d, J=4.84 Hz).
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][O:9][C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1.Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>O1CCCC1>[CH3:8][O:9][C:10](=[O:20])[CH:11]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
2.5M nButyllithium in hexanes (37.5 ml, 0.094 mol) was added, in a dropwise fashion, to a solution of diisopropylamine (14.45 ml, 0.103 mol) in tetrahydrofuran (300 ml) at 0° C. The solution was stirred at 0° C. for 20 minutes. The mixture was then cooled to −70° C. and a solution of (3,4-dichloro-phenyl)-acetic acid methyl ester (20.54 g, 0.094 mol) in tetrahydrofuran (50 ml) was added dropwise via cannula. The reaction mixture was stirred at −70° C. for 30 minutes. After this time, tert-butyl bromoacetate (45.42 ml, 0.281 mol) was added in a dropwise fashion. The cooling bath was removed and the reaction mixture was allowed to warm up to room temperature. The reaction mixture was quenched with a saturated solution of NH4Cl (100 ml). THF was partially removed in vacuo and the mixture was extracted with EtOAc (3×200 ml). The combined organic extrats were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by silica gel column chromatography using as eluent petrol: ether (9:1) to give the title compound in 92% yield.). 1H NMR (400 MHz, DMSO-d6) δ 1.34 (9H, s), 2.65 (1H, dd), 2.98 (1H, dd), 3.60 (3H, s), 4.08 (1H, m), 7.31 (1H, m), 7.58–7.62 (2H, m); MS (ES+): m/e=333.2 (5%); MS (ES−): m/e=331.2 (100%), 333.2 (65%), 335.2 (10%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[N:3]=1.O.[NH2:11][NH2:12]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[NH:9])[NH:11][NH2:12])[N:3]=1
Reactant: NN
Reactant: Cc1ccnc(C#N)n1
Solvent: O
Solvent: CCO
Product: Cc1ccnc(C(=N)NN)n1

Procedure:
4-methyl-2-pyrimidinecarbonitrile (I98)(0.190 g, 1.595 mmol) was dissolved in ethanol (3.19 ml) and hydrazine hydrate (0.100 ml, 3.19 mmol) was added. The reaction mixture was left at reflux for 2.5 hours. TLC showed that no starting material remained so the solvent was removed under reduced pressure to afford the crude desired product in 247 mg.
Reaction SMILES: [H-].[Na+].[CH2:3]1COCC1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]3[C:30](=[O:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=[N:26]3)[CH2:19][CH2:18]2)=[CH:9]1.IC>O>[CH3:3][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]3[C:30](=[O:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=[N:26]3)[CH2:19][CH2:18]2)=[CH:9]1
Reactant: C1CCOC1
Reactant: O=c1c2ccccc2nnn1CCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1cc(C2CCN(CCn3nnc4ccccc4c3=O)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
A dried flask under nitrogen was loaded with sodium hydride (0.015 g, 0.37 mmol) and THF (10 mL). At 0° C. 3-{2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl}-1,2,3-benzotriazin-4(3H)-one (0.07 g, 0.19 mmol), was added and the mixture stirred for 15 minutes. Keeping the reaction temperature at 0° C., the iodomethane was added dropwise (0.01 mL, 0.19 mmol). This was allowed to warm to room temperature and stir overnight. Water was slowly added to the mixture to quench and the organics were extracted in chloroform, washed with water and dried over Na2SO4, filtered and concentrated. The residue was chromatographed using silica and a 2% methanol:chloroform system. 0.03 g of 3-{2-[4-(1-methyl-1H-indol-3-yl)-1-piperidinyl]ethyl}-1,2,3-benzotriazin-4(3H)-one was isolated as an orange solid. Yield 41%; MS: 388.3 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 1.80 (q, 2H), 2.03 (d, 2H), 2.31 (t, 2H), 2.81 (m, 1H), 2.96 (t, 2H), 3.16 (d, 2H), 3.73 (s, 3H), 4.68 (t, J=5.19 Hz, 2H), 6.79 (s, 1H), 7.06 (t, 1H), 7.20 (t, 1H), 7.28 (m, 1H), 7.60 (d, 1H), 7.81 (t, 1H), 7.95 (t, 1H), 8.16 (d, 1H), 8.37 (d, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:33])[C@H:5]([CH2:29][CH2:30][S:31][CH3:32])[NH:6][C:7](=[O:28])[CH2:8][N:9]([CH2:21][C@@H:22]([NH2:27])[CH:23]([CH3:26])[CH2:24][CH3:25])[CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[CH2:34]([O:41][CH2:42][C:43](Cl)=[O:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:2][O:3][C:4](=[O:33])[C@H:5]([CH2:29][CH2:30][S:31][CH3:32])[NH:6][C:7](=[O:28])[CH2:8][N:9]([CH2:21][C@@H:22]([NH:27][C:43](=[O:44])[CH2:42][O:41][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@@H:23]([CH3:26])[CH2:24][CH3:25])[CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CCC(C)[C@H](N)CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12
Agent: Cl
Product: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12)NC(=O)COCc1ccccc1

Procedure:
The title compound was prepared from N-[2(S)-amino-3-methylpentyl)-N-(1-naphthylmethyl)-glycyl-methionine methyl ester hydrochloride (Example 1, Step E) and benzyloxyacetyl chloride (Aldrich) under standard conditions.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH2:20][Cl:21]>>[Cl:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C=Cc2cccc(Cl)c2)cc1
Reactant: ClCCCBr
Product: ClCCCOc1ccc(/C=C/c2cccc(Cl)c2)cc1
Yield: 86.3 %

Procedure:
The procedures of Example 1 were followed using 4-hydroxy-3'-chlorostilbene (5.0 g, 23 mmol) and 1-bromo-3-chloropropane (4.4 mL, 43 mmol) to give 6.1 g (87%) of (E)-4-chloropropoxy-3'-chlorostilbene as an amber oil. 1NMR (CDCl3): δ7.66-6.72(m,10H), 4.11(t,2H), 3.72(t,2H), 2.22(m,2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Cl.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16].C(N(CC)CC)C.O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:20][CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:21])=[O:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C=Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CNC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
A solution of 4-fluoro-3-nitrophenyl isocyanate (10 g, 0.055 mol) in anhydrous tetrahydrofuran is cooled to 0° C., treated with glycine ethyl ester hydrochloride (7.7 g, 0.055 mol), treated with triethylamine (5.56 g, 0.055 mol) while maintaining the temperature below 10° C., stirred at room temperature for 1 hour and poured into water. The aqueous mixture is extracted with ether. The combined organic extracts are washed sequentially with 1N hydrochloric acid and brine, dried over anhydrous. magnesium sulfate, and concentrated in vacuo to obtain a solid which is air-dried to give the title product as a yellow solid (8.8 g, mp 115°-120° C.).
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[C:18]([C:21]12[CH2:31][C:25]3([OH:32])[CH2:26][C:27]([OH:30])([CH2:29][C:23]([C:33]([OH:35])=[O:34])([CH2:24]3)[CH2:22]1)[CH2:28]2)([OH:20])=[O:19]>>[C:33]([C:23]12[CH2:24][C:25]3([O:32][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:26][C:27]([OH:30])([CH2:28][C:21]([C:18]([OH:20])=[O:19])([CH2:31]3)[CH2:22]1)[CH2:29]2)([OH:35])=[O:34]
Reactant: O=C(O)C12CC3(O)CC(O)(C1)CC(C(=O)O)(C3)C2
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Product: C=CC(=O)OC12CC3(O)CC(C(=O)O)(C1)CC(C(=O)O)(C3)C2
Yield: 86 %

Procedure:
The reaction was conducted in the same manner as said (2) except that 1,3-dicarboxy-5,7-dihydroxyadamantane was used instead of the 1,3-dicarboxy-5-adamantanol, and, as a result, a 1,3-dicarboxy-5-acryloyloxy-7-adamantanol (yield: 86%, white solid) was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[S:33](Cl)(=[O:35])=[O:34]>>[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[S:33]([O:26][C:11]1[N:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=1[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:27])[NH:6]2)(=[O:35])=[O:34]
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12
Reactant: O=S(=O)(Cl)c1cccs1
Product: CC(=O)C1=C(C)Nc2ccnc(OS(=O)(=O)c3cccs3)c2C1c1cccc2c(=O)cc(C)oc12

Procedure:
The title compound is prepared in analogy to example 10 from 50 mg (0.13 mmol) of 3-acetyl-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-4,6-dihydro-1,6-naphthyridin-5(1H)-one and 28 mg (0.15 mmol) of thiophene-2-sulfonyl chloride. 57 mg (81% of theory) of the product are obtained as a pale yellow solid.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.C1(C#C)C=CC=CC=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[C:27]#N>C(#N)C1C=CC=CC=1>[C:27]([C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=1)#[C:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: N#Cc1ccc2ccccc2c1
Reactant: C#CCCCCCC
Solvent: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CCCCCCC#Cc1ccc2ccccc2c1
Reaction time: 22 h
Yield: 99 %

Procedure:
The procedure was identical to Example 2, with the exception that 1-octyne (0.590 ml; 0.441 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 2-naphthonitrile (0.306 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 22 h at 65° C. showed the presence of 1.98 mmol (99% yield) of 2-(1-octynyl)naphthalene and no remaining 2-naphthonitrile in the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1([OH:34])[C:17]2[C:12](=[CH:13][C:14]([I:22])=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:23][C@H:24]2[CH2:27][C@H:26]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:25]2)[C:10]1=[O:33].[CH3:35][O:36][C@@H:37]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:38]([OH:40])=[O:39].CCCCCC>C(OCC)(=O)C>[CH3:35][O:36][C@@H:37]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:38]([O-:40])=[O:39].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1([OH:34])[C:17]2[C:12](=[CH:13][C:14]([I:22])=[CH:15][C:16]=2[C:18]([F:20])([F:21])[F:19])[N:11]([CH2:23][C@H:24]2[CH2:25][C@H:26]([N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])[CH2:27]2)[C:10]1=[O:33]
Reactant: CO[C@H](C(=O)O)c1ccccc1
Agent: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3c(F)cccc3Cl)c3c2cc(I)cc3C(F)(F)F)C1
Agent: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3c(F)cccc3Cl)c3c2cc(I)cc3C(F)(F)F)C1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CO[C@H](C(=O)[O-])c1ccccc1
Temperature: 6 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-chloro-6-fluorophenyl)-1-[trans-3-(diethylamino)-cyclobutylmethyl]-4-trifluoromethyl-3-hydroxy-6-iodo-1,3-dihydro-2H-indol-2-one (3.60 g, 5.89 mmol) in ethyl acetate (50 mL) was added (S)-α-methoxyphenylacetic acid (550 mg), and the mixture was heated to 6° C. and stirred for 1 hour. Then, the mixture was stirred at room temperature for 1 hour, and thereto was added hexane (10 mL), and the mixture was stirred for additional 30 minutes at room temperature. The precipitated solid was filtered (1.41 g). The solid was recrystallized from ethyl acetate (20 mL)/hexane (3.0 ml) to give (S)-methoxyphenylacetate of 3-(2-chloro-6-fluorophenyl)-1-[trans-3-(diethylamino)-cyclobutylmethyl]-4-trifluoromethyl-3-hydroxy-6-iodo-1,3-dihydro-2H-indol-2-one (970 mg). The resulting compound was converted to its nonsalt form. Thus, the titled compound (650 mg, 98% ee, 18% y.) was obtained.