Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([OH:14])=[C:8]([O:15][CH3:16])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:24][CH3:25].Cl>CN(C=O)C.O.CCOC(C)=O>[CH2:24]([O:14][C:9]1[C:8]([O:15][CH3:16])=[CH:7][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:11][C:10]=1[O:12][CH3:13])[CH3:25]
Reactant: CCI
Reactant: COc1cc(-c2ccco2)cc(OC)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1c(OC)cc(-c2ccco2)cc1OC
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 92.2 %

Procedure:
To a suspension of 4-(furan-2-yl)-2,6-dimethoxyphenol (0.493 g, 2.24 mmol) in anhydr DMF (10 mL) under argon was added Cs2CO3 (1.2 g, 3.7 mmol) and iodoethane (0.22 mL, 2.7 mmol). The mixture was stirred for 20 min then heated at 80° C. for 2 hrs. After cooling to room temperature, the reaction was diluted with H2O and EtOAc then it was acidified with the addition of 6 M HCl. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were diluted with hexanes and washed with H2O and brine, dried over Na2SO4 and filtered through a pad of silica gel on Celite. The filtrate was concentrated in vacuo to give 2-(4-ethoxy-3,5-dimethoxyphenyl)furan as a beige solid (0.513 g, 92% yield). The product was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C@@H:6]([C:15]([O:17]C)=O)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[OH-].[Na+].Cl.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(OCC)(=O)C.O1CCOCC1>[O:17]=[C:15]1[CH:6]([NH:7][C:8](=[O:9])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5][S:4][CH2:3][CH2:2][NH:1]1
Reactant: COC(=O)[C@H](CSCCN)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CSCCNC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of S-(2-aminoethyl)-N-[(1,1-dimethylethoxy)carbonyl]-L-cysteine, methyl ester (7.5 g., 26.9 mmole), 1N sodium hydroxide (31.0 ml., 1.15 eq.), and dioxane (30 ml.) is stirred at room temperature for 2 hours. The reaction is then treated with 1N hydrochloric acid (4.1 ml.) to quench excess hydroxide. The dioxane and water are evaporated and the residual water is removed azeotropically with acetonitrile (twice). The resulting foam is taken into dry dimethylformamide (100 ml.), treated with diphenylphosphoryl azide (6.5 ml., 1.1 eq.), and stirred under argon at 25° for 3.5 days. The reaction mixture is diluted with ethyl acetate and washed successively with water, saturated sodium bicarbonate, 5% potassium bisulfate, brine, dried (MgSO4), and evaporated. The residue (3.0 g.) is taken up in hot ethyl acetate and upon cooling 1.1 g. of the product crystallizes as a colorless solid. The mother liquor (1.9 g.) is chromatographed on silica (70 g.) eluting with 5% acetone/methylene chloride to give an additional 0.4 g. of product as a slightly colored solid. A small portion of the product is recrystallized from toluene to give (hexahydro-5-oxo-1,4-thiazepin-6-yl)carbamic acid, (1,1-dimethylethyl) ester as fine colorless needles; m.p. 199.5°-201°. TLC (10% acetone/methylene chloride) single spot at Rf =0.49.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[C:11]([O:12][CH2:13][CH3:14])=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)#[N:2].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[C:1]([C:3]1[O:4][C:5]2[C:11]([O:12][CH2:13][CH3:14])=[CH:10][CH:9]=[C:8]([S:16]([Cl:15])(=[O:18])=[O:17])[C:6]=2[CH:7]=1)#[N:2]
Reactant: CCOc1cccc2cc(C#N)oc12
Reactant: O=S(=O)(O)Cl
Product: CCOc1ccc(S(=O)(=O)Cl)c2cc(C#N)oc12
Yield: 43 %

Procedure:
There was reacted 1 g (5.4 mmole) of 2-cyano-7-ethoxybenzofuran (with chlorosulfonic acid as in Example 1, yielding 0.65 g of 2-cyano-4-chlorosulfonyl-7-ethoxybenzofuran (yield: 43%, MS (m/z): 285 (M+), 257, 250 and 222). The obtained chlorosulfonyl compound was reacted with glycine ethyl ester hydrochloride as in Example 1 to give an ester compound (yield: 46%, MS (m/z): 385 (M+), 279, 250 and 222), which was then hydrolyzed, accompanying the hydrolysis of nitrile, to give 2-carboxy-4-(N-carboxymethylsulfamoyl)-7-ethoxybenzofuran (yellow prisms, yield: 62%). The physical constants are shown in Table 4.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[I-].[K+].Cl[C:21]([CH3:25])([CH3:24])[C:22]#[CH:23].[OH-].[Na+]>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][C:21]([CH3:25])([CH3:24])[C:22]#[CH:23])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC(C)=O)cc1O
Reactant: C#CC(C)(C)Cl
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CC(C)(C)Oc1cc(NC(C)=O)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
To a solution of 310 parts of methyl 4-(acetylamino]-2-hydroxybenzoate in 2820 parts of N,N-dimethylformamide there were added portion wise 71 parts of a dispersion of sodium hydride in mineral oil (50%) and, after stirring for 1 hour at room temperature, one crystal of potassium iodide and 172 parts of 3-chloro-3-methyl-1-butyne under a nitrogen atmosphere. The whole was stirred for 24 hours at 90° C. and was then poured into NaOH 10% (aq.). The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was successively stirred in petroleumether and dissolved in dichloromethane. The latter solution was washed with water, NaOH 10% and water and was then dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2). The eluent of the desired fraction was evaporated, yielding in two fractions 41 parts (10.1%) of methyl 4-(acetylamino)-2-(1,1-dimethyl-2-propynyloxy)benzoate (interm. 1).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH:27]1([CH2:30][C:31](O)=[O:32])[CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][CH:27]3[CH2:29][CH2:28]3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)CC1CC1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(CC1CC1)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, light yellow solid (74 mg, 73%), MS (ISP) m/z=409.4 [(M+H)+], mp 165° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2-cyclopropyl-acetic acid.
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Br:21])=[N:12][N:13]([CH:18]([CH3:20])[CH3:19])[C:14]2=[O:17])=[CH:9][CH:8]=1.N([O-])=[O:23].[Na+].NC(N)=O>CC(O)=O.O>[OH:23][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Br:21])=[N:12][N:13]([CH:18]([CH3:20])[CH3:19])[C:14]2=[O:17])=[CH:9][CH:8]=1
Reactant: O=N[O-]
Reactant: CC(C)n1nc(Br)c2ccc(N)cc2c1=O
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)n1nc(Br)c2ccc(O)cc2c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
Concentrated sulfuric acid (17 ml) was added slowly to a solution of 7-Amino-2-Isopropyl-4-bromo-2H-phthalazin-1-one (4.6 g, 0.016 mol) in HOAc (50 ml). The reaction mixture was cooled to 0° C. and a solution of NaNO2 (1.52 g, 0.022 mol) in water (10 ml) was added dropwise. The reaction mixture was stirred for a further 20 min at 0° C. prior to the addition of urea (0.55 g, 0.009 mol) and cold water (50 ml). The reaction mixture was then added carefully to a refluxing mixture of sulfuric acid (28 ml) in water (115 ml) and the reaction was stirred for a further 10 min at reflux before being allowed to cool to RT. Upon standing, an orange precipitate was observed, which was collected by filtration and washed with water to give the title compound (4.22 g, 93% yield) as an orange powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:24])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:17]=[N:18][C:19]([F:23])=[CH:20][C:21]=3[CH3:22])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1>>[CH:25]1([C:2]2[CH:3]=[C:4]([CH3:24])[C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([C:16]4[CH:17]=[N:18][C:19]([F:23])=[CH:20][C:21]=4[CH3:22])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH2:27][CH2:26]1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(Br)cc2C)CC1
Reactant: OB(O)C1CC1
Product: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 120.5 %

Procedure:
Using [4-(5-bromo-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (2.2 g) described in Preparation Example 139 and cyclopropylboronic acid (721 mg) and by the reaction and treatment in the same manner as in Preparation Example 100, the title compound (2.39 g) was obtained.
Reaction SMILES: C(N1CCN(C2C=[C:11]([NH:15][C:16]([C:18]3[C:19]4[N:20]=[CH:21][CH:22]=[N:23][C:24]=4[C:25]([C:28]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30]C=4Cl)=[CH:26][CH:27]=3)=[O:17])C=CC=2)CC1)C.[CH2:37]([Cl:39])Cl.CO>>[NH:20]1[CH:19]=[CH:24][N:23]=[C:11]1[NH:15][C:16]([C:18]1[C:19]2[N:20]=[CH:21][CH:22]=[N:23][C:24]=2[C:25]([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:37]=2[Cl:39])=[CH:26][CH:27]=1)=[O:17]
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cc(OC)ccc4Cl)c4nccnc34)c2)CC1
Reactant: ClCCl
Solvent: CO
Product: COc1ccc(Cl)c(-c2ccc(C(=O)Nc3ncc[nH]3)c3nccnc23)c1

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-(2-chloro-5-methoxy-phenyl)-quinoxaline-5-carboxylic acid (Example 63) in Step 14.1. Title compound: ESI-MS: 380.0 [M+H]+; tR=3.61 min (System 1); TLC: Rf=0.36 (DCM/MeOH, 95:5).
Reaction SMILES: [CH3:1][Si](C)(C)N[Si](C)(C)C.C([Li])CCC.CCCCCC.Br[C:22]1[N:36]([Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C:35]2[C:44]3[C:23]=1[CH2:24][C@@H:25]1[C:30]([C:31]=3[CH:32]=[CH:33][CH:34]=2)=[CH:29][C@H:28]([NH:45][C:46](=[O:52])[N:47]([CH2:50][CH3:51])[CH2:48][CH3:49])[CH2:27][N:26]1[CH3:53].CN(C)CCN(C)C.C([Li])(C)(C)C.FC(F)(F)S(O)(=O)=O>O.C1(C)C=CC=CC=1>[Si:37]([N:36]1[C:35]2[C:44]3[C:23]([CH2:24][C@@H:25]4[C:30]([C:31]=3[CH:32]=[CH:33][CH:34]=2)=[CH:29][C@H:28]([NH:45][C:46](=[O:52])[N:47]([CH2:50][CH3:51])[CH2:48][CH3:49])[CH2:27][N:26]4[CH3:53])=[C:22]1[CH3:1])([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4c3c(c(Br)n4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: CN(C)CCN(C)C
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4c3c(c(C)n4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27.4 %

Procedure:
Under argon, 0.3 ml (1.5 mmol) of distilled hexamethyldisilazane is added to 4 ml of absolute, freshly distilled toluene, and the mixture is cooled to 0° C. Then 0.85 ml (1.4 mmol) of 15% butyllithium/hexane is added dropwise and the mixture is stirred for 15 minutes at 0° C. To this mixture is added 531 mg (1 mmol) of 3-[2-bromo-1-(tert-butyldimethylsilyl)-9,10-didehydro-6-methyl-8α-ergolinyl]-1,1-diethylurea in 50 ml of absolute, freshly distilled toluene and agitation is continued for another 15 minutes at 0° C. After adding 1 ml of distilled tetramethylethylenediamine, the batch is cooled to -90° C. At this temperature, 5 ml (7 mmol) of 1.4M tert-butyllithium is added and the mixture is agitated for 2 minutes before 0.6 ml (5.4 mmol) of the methyl ester of trifluoromethanesulfonic acid is added thereto. After 11/2 hours of agitation at -70° C., water is added to work up the reaction mixture. Extraction is performed with ethyl acetate. The organic phases are washed with saturated sodium bicarbonate solution and water. The combined ethyl acetate phases are dried over sodium sulfate and concentrated. Crystallization from methanol produces 128 mg of 3-[1-(tert-butyldimethylsilyl)-9,10-didehydro-2,6-dimethyl-8α-ergolinyl]-1,1-diethylurea (27% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH:4]=[C:5]([C:10]([CH3:12])=O)[C:6]([O:8][CH3:9])=[O:7].[NH2:17]/[C:18](/[CH2:25][O:26][CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])=[CH:19]\[C:20]([O:22][CH2:23][CH3:24])=[O:21].CO>CC(O)C>[CH3:24][CH2:23][O:22][C:20]([C:19]1[CH:4]([C:3]2[C:2]([Cl:1])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([CH3:12])[NH:17][C:18]=1[CH2:25][O:26][CH2:27][CH2:28][N:29]1[C:30](=[O:39])[C:31]2[C:32](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:34])=[O:21]
Reactant: CCOC(=O)/C=C(\N)COCCN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)C(=Cc1ccccc1Cl)C(C)=O
Solvent: CC(C)O
Solvent: CO
Product: CCOC(=O)C1=C(COCCN2C(=O)c3ccccc3C2=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 0 °C
Yield: 69.6 %

Procedure:
Methyl 2-(2-chlorobenzyliden)acetoacetate (40.6 g; 169.9 mmol) was condensed with ethyl 3-amino-4-[2-(phthalimido)ethoxy]crotonate (51.5 g; 161.8 mmol) in 2-propanol (160 ml) under reflux for 11 hours. Methanol (103 ml) was added and mixture was cooled to 5/0° C. The solid was filtered off and dried at 40° C. Phthaloyl Amlodipine (60.7 g, purity: 98.6%; 0.86% of impurity HA) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][C:26]([CH:32]4[CH2:34][CH2:33]4)=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1>>[CH:29]1([C:28]2[C:23]([N:20]3[CH2:21][CH2:22][N:17]([C:15]([C:12]4[N:13]=[CH:14][C:9]([N:4]5[CH2:5][CH2:6][N:2]([CH3:1])[C:3]5=[O:7])=[CH:10][CH:11]=4)=[O:16])[CH2:18][CH2:19]3)=[N:24][CH:25]=[C:26]([CH:32]3[CH2:34][CH2:33]3)[CH:27]=2)[CH2:31][CH2:30]1
Reactant: O=C(c1ccc(Br)cn1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: CN1CCNC1=O
Product: CN1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)nc2)C1=O
Yield: 34.6 %

Procedure:
Using 1-methyl-2-imidazolidinone (181 mg) and (5-bromopyridin-2-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (700 mg) described in Preparation Example 142 and by the reaction and treatment in the same manner as in Example 1, the title compound (253 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]([CH3:13])([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:9][C:8](=[O:10])[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][CH:4]=2)([CH3:13])[CH2:11][CH3:12])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: CCC(C)(Oc1ccc(C)cc1)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCC(C)(Oc1ccc(C)cc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 85 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 600 mg of (2RS)-2-(4-methylphenoxy)-2-methylbutyric acid and 1.32 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-napthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.51 g of the title compound as a colorless foam.
Reaction SMILES: [C:1]([Sn:5]([Cl:11])(Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[F-:12].[Na+]>C(O)C>[C:1]([Sn:5]([Cl:11])([F:12])[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: CC(C)(C)[Sn](Cl)(Cl)C(C)(C)C
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[Sn](F)(Cl)C(C)(C)C

Procedure:
An ethereal solution of di-t-butyltin dichloride (10 g., 50 ml.) was shaken vigorously with a filtered solution of sodium fluoride (3 g.) in aqueous ethanol (50 ml.). The white solid formed at the interface, was filtered, and washed with 95% ethanol followed by ether (7.0 g., 74%); the solid turns light brown at 254° but does not melt. (Found: C, 33.4; H, 6.4; Cl, 9.2; F, 8.7; Sn, 43.3. C8H18ClFSn requires C, 33.45; H, 6.3; Cl, 12.25; F, 6.65; Sn, 41.3%.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[OH:28][C:29]([CH3:42])([C:33]([NH:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[O:34])[C:30](O)=[O:31]>>[CH2:13]([O:12][CH2:11][CH2:10][N:7]1[C:8](=[O:9])[C@@H:2]([NH:1][C:30](=[O:31])[C:29]([OH:28])([CH3:42])[C:33]([NH:35][CH2:36][CH2:37][C:38]([F:41])([F:39])[F:40])=[O:34])[C:3]2[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=2[C:5]2[CH:23]=[CH:22][CH:21]=[CH:20][C:6]1=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(O)(C(=O)O)C(=O)NCCC(F)(F)F
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: CC(O)(C(=O)NCCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2-hydroxy-2-methyl-N-(3,3,3-trifluoro-propyl)-malonamic acid, the title compound was prepared in the same manner as described for example 1c. Colorless, viscous oil (73%). MS: m/e=570(M+H+).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:5]=[C:6]2[N:11]([CH:12]=1)[CH:10]=[C:9]([C:13]#[N:14])[CH:8]=[CH:7]2>CN(C)C=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:1][C:12]1[N:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]2)=[CH:5][C:4]=1[CH3:3]
Reactant: Cc1cc2ccc(C#N)cn2c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2ccc(C#N)cn2c1Br
Temperature: 80 °C
Yield: 66.5 %

Procedure:
A solution of bromine (0.33 ml, 6.40 mmol. 1.0 equiv) in 10 ml of N,N-dimethylformamide is added under an atmosphere of argon at 0° C. to a solution of 2-methyl-indolizine-6-carbonitrile (1.0 g, 6.40 mmol) in 5 ml of N,N-dimethylformamide. The reaction mixture is heated in a microwave for 3 minutes at 80° C. After cooling, the reaction mixture is diluted with EtOAc and concentrated aqueous NaHCO3 solution. The aqueous phase is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatography (hexane/EtOAc 4:1, +0.2% NEt3) affords the title compound (1.0 g, 53%). 1H NMR (400 MHz, d6-DMSO): δ=8.97 (t, J=1.4 Hz, 1H), 7.56 (s, 1H), 7.28 (d, J=9.3 Hz, 1H), 6.87 (dd, J=9.3/1.5 Hz, 1H), 2.15 (d, J=1.0 Hz, 3H). MS (ES+): 236 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[CH:11][CH:10]=[C:9]([C@@H:13]([OH:24])[C@H:14]3[N:19]4[CH2:20][C@H:21]([CH:22]=[CH2:23])[C@@H:16]([CH2:17][CH2:18]4)[CH2:15]3)[C:7]=2[CH:8]=1.C(N(CC)CC)C.ClCCl.[F:35][C:36]([F:42])([F:41])[S:37](Cl)(=[O:39])=[O:38]>C(#N)C.O.C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[CH:11][CH:10]=[C:9]([C@@H:13]([OH:24])[C@H:14]3[N:19]4[CH2:20][C@H:21]([CH:22]=[CH2:23])[C@@H:16]([CH2:17][CH2:18]4)[CH2:15]3)[C:7]=2[CH:8]=1.[O-:38][S:37]([C:36]([F:42])([F:41])[F:35])(=[O:2])=[O:39]
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A two-necked flask (internal volume: 30 mL) charged with magnetic stir bars was charged with demethylated quinine (quinine-OH) (465.6 mg, 1.5 mmol). The flask was cooled to 0° C., triethylamine (238 μL, 1.1 equiv.), dichloromethane (3.0 mL), and trifluoromethanesulfonyl chloride (166 μL, 1.05 equiv.) were added to the flask, and the mixture was reacted at room temperature with stirring. After 8 hours, the reaction was quenched by adding a saturated sodium hydrogen carbonate aqueous solution (5 mL) to the reaction mixture, and the reaction mixture was separated into two layers. The organic layer (dichloromethane solution) was isolated preparatively, and 15 mL of dichloromethane was added to the aqueous layer to extract the product. The above operation was repeated four times. An excess amount of anhydrous magnesium sulfate was added to the collected organic layer (dichloromethane solution), and the mixture was filtered. The solvent was evaporated under reduced pressure to obtain a concentrate including a crude product. The concentrate was sequentially subjected to silica gel flash column chromatography (eluant: chloroform/methanol=9/1, Rf=0.26)) and reversed-phase high-performance liquid chromatography (eluant: water and acetonitrile (gradient)) to obtain quinine triflate (white solid, 265.9 mg) (see below). The yield thereof was 40%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[C:12]1([C:18]2[N:19]=[CH:20][NH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.N1C=CC=CC=1>CN(C)C=O.ClCCl.N.C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[C:12]1([C:18]2[N:19]=[CH:20][N:21]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=3)[CH:22]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: OCc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCc1ccc(-n2cnc(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.7 %

Procedure:
3.04 g (20 mmol) of 4-(hydroxymethyl)phenylboronic acid, 1.44 g (10 mmol) of 4-phenylimidazole, 2.8 ml (20 mmol) of triethylamine and 1.64 ml (20 mmol) of pyridine are dissolved in 20 ml of dimethylformamide. 2.72 g (15 mmol) of copper diacetate are added and the mixture is stirred for 24 hours at ambient temperature. It is diluted with 200 ml of dichloromethane and 200 ml of aqueous 28% ammonia solution. After the phases have settled and been separated, the aqueous phase is extracted with 100 ml of dichloromethane. The organic phases are washed with 50 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The product is purified by chromatography on silica gel, eluting with a 97/3 then 95/5 mixture of dichloromethane and methanol. The product is recrystallized from a mixture of toluene and diisopropyl ether, to give 1.82 g of product in the form of white crystals.