Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH2:17].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH:17][C:1](=[O:11])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: COC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cinnamic acid (38.0 g) was coupled to glycine methyl ester hydrochloride in dimethylformamide by treatment with dicyclohexylcarbodiimide (52.84 g) and 1-hydroxybenzotriazole (39.24 g), followed by N-methylmorpholine (37.56 ml). The reaction mixture was stirred overnight at room temperature and then worked up in the usual manner to give the desired product.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[C:12](=[O:23])[CH:13]([CH2:16][C:17]3[N:18]=[CH:19][NH:20][C:21]=3[CH3:22])[CH2:14][CH2:15][C:4]=12)[CH3:2].[C:24](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C)C=O.O>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[C:12](=[O:23])[CH:13]([CH2:16][C:17]3[N:18]=[CH:19][N:20]([C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:21]=3[CH3:22])[CH2:14][CH2:15][C:4]=12)[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1c2n(c3ccccc13)C(=O)C(Cc1nc[nH]c1C)CC2
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1c2n(c3ccccc13)C(=O)C(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.9 %

Procedure:
A mixture of 8,9-dihydro-10-ethyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]-indol-6(7H)-one (0.84 g), trityl chloride (1.0 g) and triethylamine (515 mg) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 18 hours. The reaction mixture was diluted with chilled water and extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Purification of the residue with silica gel column chromatography (2% methanol-chloroform) gave 8,9-dihydro-10-ethyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]-indol-6(7H)-one (690 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])/[N:4]=[N:5]/[C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:10]([C:19](=[O:21])[CH3:20])[CH:9]=[C:8]([F:22])[C:7]=1[C:23]#[C:24][Si](C)(C)C)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO>[CH2:29]([N:3]([CH2:1][CH3:2])/[N:4]=[N:5]/[C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:10]([C:19](=[O:21])[CH3:20])[CH:9]=[C:8]([F:22])[C:7]=1[C:23]#[CH:24])[CH3:30]
Reactant: CCN(CC)/N=N/c1c(C#C[Si](C)(C)C)c(F)cc(C(C)=O)c1-c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1c(F)cc(C(C)=O)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A solution of 1-{6-[(1E)-3,3-diethyltriaz-1-en-1-yl]-3′,4-difluoro-5-[(trimethylsilyl)ethynyl]biphenyl-2-yl}ethanone (2.0 g, 4.6 mmol) in tetrahydrofuran (39 mL) and methanol (7.7 mL) was treated with powdered potassium carbonate (3.2 g, 23 mmol) and stirred at 0° C. for 2 hours. The reaction mixture was filtered and the filtrate was treated with a few drops of water. The filtrate was concentrated to an oil that was diluted with ethyl acetate (150 mL), washed with water (50 mL) and brine (25 mL), dried with sodium sulfate, filtered, and concentrated to give the desired product (1.6 g, 99%) that was used without further purification. LCMS for C20H20F2N3O (M+H)+: m/z=356.2; Found: 355.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=O)[O:8]2.CO[CH2:16][N:17](CC1C=CC=CC=1)[CH2:18][Si](C)(C)C>>[CH3:1][O:2][C:3]1[C:4]2[C@@H:5]3[CH2:18][NH:17][CH2:16][C@@H:6]3[CH2:7][O:8][C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COc1cccc2oc(=O)ccc12
Product: COc1cccc2c1[C@@H]1CNC[C@@H]1CO2

Procedure:
From 5-methoxycoumarin and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine in an analogous manner as described in Examples 1A-C. 1H NMR (300 MHz, CDCl3) δ 2.55 (m, 1H), 2.67 (dd, 1H), 2.80 (dd, 1H), 3.21 (q, 1H), 3.32 (dd, 1H), 3.62 (dd, 1H), 3.70 (m, 1H), 3.81 (s, 3H), 4.10 (dd, 1H), 6.46 (d, 1H), 6.55 (d, 1H), 7.17 (t, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[CH:11]1([CH2:16][C:17](Cl)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH:6][C:17](=[O:18])[CH2:16][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([CH3:10])[CH:3]=1
Reactant: O=C(Cl)CC1CCCC1
Reactant: Cc1cc(Br)cc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1NC(=O)CC1CCCC1
Yield: 99 %

Procedure:
4-Bromo-2,6-dimethyl-aniline (4.3 g) and cyclopentylacetyl chloride (3.46 g) were mixed in acetonitrile (50 mL) and tetrahydrofuran (20 mL) and the reaction mixture was heated to reflux for 1 hour. Potassium carbonate (4.5 g) was added and the reaction mixture was refluxed for 1 hour and then poured onto crushed ice and saturated aqueous potassium carbonate (50 mL). The product was collected by filtration and washed with water (100 mL) to furnish 6.6 g (100% yield) of the title compound as a solid. LC-MS (m/z) 311 (MH+); tR=3.07, (UV, ELSD) 100%, 100%. 1H NMR (500 MHz, DMSO-d6): 1.21 (m, 2H), 1.52 (m, 2H), 1.61 (m, 2H), 1.77 (m, 2H), 2.11 (s, 6H), 2.25 (m, 1H), 2.31 (d, 2H), 7.27 (s, 2H), 9.23 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[CH3:22][N:23]([CH3:29])[CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>C1COCC1>[CH3:22][N:23]([CH3:29])[CH:24]1[CH2:28][CH2:27][N:26]([C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:25]1
Reactant: CN(C)C1CCNC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-nitrobenzoyl chloride (1.8 g, 10 mmol) and diisopropylethylamine (2.8 mL, 20 mmol) in THF at room temperature is added 3-(dimethylamino)pyrrolidine (1.4 mL, 11 mmol). The reaction is stirred for 2 hours at room temperature and concentrated in vacuo to give 3-dimethylamino-1-(4-nitrobenzoyl)pyrrolidine, identified by HPLC and MS [264.3 m/e (M+H)] analyses.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:7](Cl)[N:6]=[CH:5][N:4]=1>C(O)C>[NH2:1][C:7]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:3]([Cl:2])[N:4]=[CH:5][N:6]=1
Reactant: COc1ccccc1Oc1c(Cl)ncnc1Cl
Reactant: N
Solvent: CCO
Product: COc1ccccc1Oc1c(N)ncnc1Cl
Temperature: -78 °C
Reaction time: 50 h

Procedure:
105 ml of ammonia were passed into a solution of 7 g of 4,6-dichloro-5-(o-methoxyphenoxy)pyrimidine in 140 ml of ethanol at -78° C. The reaction mixture was stirred for 15 hours at -78° C. and for 50 hours at room temperature and then concentrated. The residue was distributed between ethyl acetate and water and the organic phase worked up. There were obtained 6.45 g of 4-amino-6-chloro-5-(o-methoxyphenoxy)pyrimidine as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[C:21]([O:32][CH2:33][CH3:34])=[CH:22][C:23]([Cl:31])=[C:24]([S:26]([NH:29][CH3:30])(=[O:28])=[O:27])[CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:35](Cl)([Cl:37])=[O:36].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:31][C:23]1[C:24]([S:26](=[O:28])(=[O:27])[NH:29][CH3:30])=[CH:25][C:20]([C:10]2[N:9]([C:35]([Cl:37])=[O:36])[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]=2)=[C:21]([O:32][CH2:33][CH3:34])[CH:22]=1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(Cl)c(S(=O)(=O)NC)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In an analogous manner as described in example 29, 5-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-2-chloro-4-ethoxy-N-methyl-benzenesulfonamide was treated with phosgene and diisopropylethylamine in methylene chloride to give 2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride. The crude carbamoyl chloride was then reacted with 1-hydroxybenzotriazole hydrate and diisopropylethylamine in methylene chloride to give the racemic 2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carboxylic acid benzotriazol-1-yl ester after purification by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.[NH2:60][C@H:61]([C:67]1[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=1)[CH2:62][C:63]([O:65][CH3:66])=[O:64]>CN1C(=O)CCC1.CCOC(C)=O>[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([NH:60][C@H:61]([C:67]2[CH:68]=[CH:69][C:70]([Cl:73])=[CH:71][CH:72]=2)[CH2:62][C:63]([O:65][CH3:66])=[O:64])=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:26])([CH3:28])[CH3:27]
Reactant: COC(=O)C[C@H](N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H](NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 82.3 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (1.157 g, 3.04 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (1 g, 2.77 mmol) and N,N-diisopropylethylamine (1.006 mL, 6.09 mmol) in NMP (10 mL) at 20° C. The resulting solution was stirred at 20° C. for 5 minutes. (S)-methyl 3-amino-3-(4-chlorophenyl)propanoate (hydrochloride) (Intermediate 20) (0.692 g, 2.77 mmol) was then added to the solution and stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with water (2×50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford (S)-methyl 3-(4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)-3-(4-chlorophenyl)propanoate (1.27 g, 82%) as a white solid. 1H NMR (399.9 MHz, DMSO-d6) δ 1.40 (9H, s), 1.99 (2H, s), 2.04-2.07 (2H, m), 2.79-2.84 (2H, m), 3.56 (3H, s), 3.60-3.66 (1H, m), 3.67-3.70 (1H, m), 4.20 (2H, t), 5.20-5.26 (1H, m), 6.73 (1H, d), 7.13 (1H, s), 7.27 (1H, t), 7.35 (4H, q), 8.14 (1H, d), 8.21 (1H, s), 11.98 (1H, s). m/z (ESI+) (M+H)+=557; HPLC tR=2.12 min.
Reaction SMILES: [H-].[Na+].[C:3]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].Cl[CH2:22][CH2:23][S:24][CH3:25].O>CN(C)C=O>[CH2:8]([O:7][C:5](=[O:6])[CH:4]([C:3]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:22][CH2:23][S:24][CH3:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CSCCCl
Reactant: CC(C)(C)OC(=O)CC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCCC(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.7 %

Procedure:
Sodium hydride (0.96 g, 50% suspension in mineral oil) was added to a stirred solution of t-butyl benzyl malonate (5 g) in dry dimethylformamide (50 ml), maintained at 0° C. under an atmosphere of nitrogen. After stirring for 15 minutes, 2-chloroethyl-methyl sulphide (2.21 g) in dimethylformamide (10 ml) was added dropwise, while the temperature of the reaction was maintained below 10° C. The reaction was allowed to warm to room temperature and stirred for 15 hours when water was cautiously added. The reaction mixture was extracted with ethyl acetate (2×100 ml), the ethyl acetate extracts were washed with water (4×), dried (Na2SO4) and evaporated to give 4-methylthio-2-t-butyloxycarbonyl-butanoic acid benzyl ester as an oil (6.4 g). This product was dissolved in trifluoroacetic acid (50 ml) with vigorous stirring at 0° C. under nitrogen. After stirring for 45 minutes, the trifluoroacetic acid was evaporated under reduced pressure at below 35° C. Final traces of trifuoroacetic acid were removed by azeotroping with carbon tetrachloride (3×20 ml), to leave an oily residue, which was dissolved in pyridine (20 ml). To this solution were added piperidine (0.44 ml) and paraformaldehyde (1.47 g), and the mixture heated at 60° C. under nitrogen for 2 hours. The reaction mixture was cautiously poured onto iced water, and the pH adjusted to 1 using concentrated sulphuric acid. The mixture was extracted with ether (2×100 ml), and the ether extracts dried (Na2SO4) and evaporated under reduced pressure to yield the crude product (5.4 g) as an oil. This was chromatographed over silica gel, eluting with a mixture of hexane and ethyl acetate, to yield the title ester as a colourless oil (1.22 g). Found: C,64.69; H,6.55. C13H16O2S (0.25 H2O) requires C,64.85; H,6.91%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([O:7][C:8](=[O:11])[C:9]#[CH:10])[CH3:6].[CH3:12][C:13]1[O:14]C=[CH:16][CH:17]=1.O.[CH2:19](Cl)Cl>>[OH:14][C:13]1[CH:17]=[CH:16][C:10]([CH3:19])=[C:9]([CH:12]=1)[C:8]([O:7][CH2:5][CH3:6])=[O:11]
Reactant: ClCCl
Reactant: C#CC(=O)OCC
Reactant: Cc1ccco1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)c1cc(O)ccc1C
Temperature: 18 °C

Procedure:
Aluminium chloride (97 g, 731 mmol) was added over 30 seconds to stirred DCM (3 L) under argon at 16° C. resulting in a temp rise to 20° C. When this had dissolved (approx 5 mins) and the temp had cooled to 18° C., ethyl-2-propynate (71.7 g, 731 mmol) was added. A solution of 2-methylfuran (60 g, 731 mmol) in DCM (600 ml) was added to the stirred solution over 35 minutes resulting in a measured exotherm 20.5° C. The exotherm was controlled by a Huber cooling unit and the observed temp range during the addition was 18° C.-20.5° C. After the addition was complete the brown reaction mixture was stirred at 20° C. After a total of 50 mins at 20° C., the reaction mixture was poured into water (3 L) and ice (1 Kg) with stirring to give a yellow mixture. This was transferred to a separating funnel and shaken vigorously. The layers were separated and the aqueous phase further extracted with DCM (1 L). The combined organic extracts were re-washed with water (1.5 L), dried (Na2SO4) and filtered through Kieselguhr. The filtrate was concentrated in vacuo to a brown/green oil. This was purified by silica gel flash chromatography on 2 Biotage 75 L columns in toluene (700 ml) and the solution split into 2 equal portions and each passed through a 75 L column, collecting 400 ml fractions and eluting with the following solvent eluant systems:
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([Br:18])=[CH:13][C:12]=2[F:19])[N:8]=[C:7]([C:20]([O:22][CH3:23])=[O:21])[C:6]=1[Cl:24])(=O)C.C(Cl)(=O)C.C([O-])(O)=O.[Na+]>CO.C1COCC1>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([Br:18])=[CH:13][C:12]=2[F:19])[N:8]=[C:7]([C:20]([O:22][CH3:23])=[O:21])[C:6]=1[Cl:24]
Reactant: COC(=O)c1nc(-c2cc(F)c(Br)cc2F)cc(NC(C)=O)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)c1nc(-c2cc(F)c(Br)cc2F)cc(N)c1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of methyl 4-acetamido-6-(4-bromo-2,5-difluorophenyl)-3-chloropicolinate (0.300 g, 0.715 mmol) in a mixture of MeOH (3.57 mL) and THF (3.57 mL) was slowly added acetyl chloride (1.017 mL, 14.30 mmol). The reaction mixture was stirred at 20° C. for 2 h. The mixture was then poured into a saturated aqueous solution of NaHCO3 and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, concentrated and dried in vacuo to afford methyl 4-amino-6-(4-bromo-2,5-difluorophenyl)-3-chloropicolinate (0.257 g, 0.681 mmol, 95%) as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.N[N:9]1[CH2:14][CH2:13][CH2:12][N:11]=[CH:10]1.[CH2:15]([O:22][C:23]([NH:25][C@@H:26]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44][C:45]([O:47]CC)=O)=[CH:37][CH:36]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[N:51](C)C=O>>[CH2:15]([O:22][C:23]([NH:25][C@@H:26]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44][C:45](=[O:47])[NH:51][C:10]2[NH:9][CH2:14][CH2:13][CH2:12][N:11]=2)=[CH:37][CH:36]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Reactant: CN(C)C=O
Reactant: NN1C=NCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
6.72 g (0.06 mol) of potassium tert-butoxide were added to a solution of 8.13 g (0.06 mol) of 1-amino-1,4,5,6-tetrahydropyrimidine hydrochloride in 100 ml of absolute dimethylformamide. After stirring at room temperature for 30 min, 7.2 g (0.015 mol) of tert-butyl (2S)-2-benzyloxycarbonylamino-3-(4-(3-ethoxycarbonylpropyloxy)phenyl)propionate were added to this solution and it was stirred at room temperature for 12 h. After removal of the solvent in vacuo, the residue was treated with 300 ml of ethyl acetate and 100 ml of water, and the organic phase was separated off, washed two times with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product thus obtained was immediately chromatographed on silica gel (dichloromethane/methanol/glacial acetic acid 10015/1). 5.4 g (60.6%) of amorphous product were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[C:16]([Mg]Br)#[CH:17]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[C:16]#[CH:17])=[CH:6][CH:7]=1
Reactant: C#C[Mg]Br
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Solvent: C1CCOC1
Product: C#CC(O)c1c(C)noc1-c1ccc(Br)cc1
Temperature: -78 °C

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.285 g, 1.07 mmol) was dissolved in THF (8 mL) and the solution was cooled to −78° C. Ethynylmagnesium bromide (0.5M in THF, 2.6 mL, 1.28 mmol) was added dropwise and the reaction was allowed to warm to room temperature. After 1 hour the reaction was quenched with aqueous ammonium chloride the submitted to standard workup to yield the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C([O:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:26]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:27])=[CH:21][CH:20]=1)C1C=CC=CC=1.Cl>CCOC(C)=O.[Pd]>[Cl-:1].[OH:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]([NH:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:26]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N+:31]([CH2:2][C:3](=[O:4])[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)([CH2:32][CH2:33]3)[CH2:30]2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1ccc(OCc2ccccc2)nc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(Nc1ccccc1)c1ccc(O)nc1)C2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
2-Chloro-1-phenylethanone (29.3 mg, 0.12 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(6-(benzyloxy)pyridin-3-yl)-2-(phenylamino)acetate (C53) (84 mg, 0.19 mmol, mixture of diastereomers) in EtOAc (4 ml). The reaction was stirred at room temperature overnight, and then a catalytic amount of 10% Pd/C (about 10 mg) and 37% HCl (0.50 ml) were added, and the reaction was hydrogenated at 20 psi for 2 hours. Pd/C is removed by filtration, and the clear solution was evaporated to dryness. The crude was purified by preparative HPLC to obtain (3R)-3-(2-(6-hydroxypyridin-3-yl)-2-(phenylamino)acetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (20.3 mg, 18% yield).
Reaction SMILES: C([Al](C[CH:11]([CH3:13])[CH3:12])CC(C)C)C(C)C.[CH2:14]=[CH2:15].C[CH:17]([CH3:21])[CH2:18][CH:19]=[CH2:20]>>[CH3:14][CH2:15][CH2:20][CH2:19][CH2:18][CH2:17][CH2:21][CH2:13][CH2:11][CH3:12]
Reactant: C=C
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Reactant: C=CCC(C)C
Product: CCCCCCCCCC

Procedure:
The polymerization of Example 10 was repeated except that in place of the organoaluminum oxy-compound, there were used 1 mmole of triisobutylaluminum and 1.4×10-3 mg atom in terms of titanium atom of the solid catalyst component [I], whereby 46.6 g of an ethylene/4-methyl-1-pentene copolymer having MFR of 0.01 g/10 min, a density of 0.912 g/cm3, an amount of decane-soluble portion of 0.10% by weight and Mw/Mn of 13.6 was obtained.
Reaction SMILES: [Cl-:1].[C:2]1([CH2:8][N+:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C)C>[CH2:15]([C:12]1[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=1)[CH3:16].[CH2:8]([Cl:1])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Cl-]
Reactant: CCc1cc[n+](Cc2ccccc2)cc1
Solvent: CC(C)O
Product: CCc1ccncc1
Product: ClCc1ccccc1

Procedure:
Following a procedure similar to that described in Example 1(a), 415 g (89%) of N-(phenylmethyl)-4-ethylpyridinium chloride obtained from 4-ethylpyridine (214 g, 2.0 mol), benzyl chloride (253 g, 2.0 mol) and isopropanol (1200 mL). The product had a melting point of 157°-162° C.
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].C(N(CC)CC)C.FC(F)(F)C(O[C:29]1[C:34]([F:35])=[C:33]([F:36])[CH:32]=[C:31]([F:37])[C:30]=1[F:38])=O>CN(C=O)C>[F:35][C:34]1[C:33]([F:36])=[CH:32][C:31]([F:37])=[C:30]([F:38])[C:29]=1[O:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:1]
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)Oc2c(F)c(F)cc(F)c2F)N1
Yield: 65 %

Procedure:
A 2.5 g (10.3 mmol) quantity of d-biotin in 20 mL anhydrous DMF under argon atmosphere was warmed to 60° C. with stirring to effect dissolution. 1.7 mL (12.5 mmol) triethylamine was added, followed by 3.4 g (12.5 mmol) 1. The mixture was stirred for 2 hours, after which the solvent was removed by rotary evaporation. The resultant semi-solid was triturated with 15 mL ether twice to produce a white solid (2.6 g, 65%). 1H-NMR. (Ref. Wilbur, D. S., Bioconj. Chem., v8 pp572-584)