Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(COC([N:12]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C@@H:23]3[CH2:27][C@H:26]([S:28][C:29]4[C@H:30]([CH3:53])[C@@H:31]5[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]5[C:33]=4[C:34]([O:36]CC4C=CC([N+]([O-])=O)=CC=4)=[O:35])[CH2:25][N:24]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:22])[CH2:17][C@@H:16]2[CH3:67])[CH3:14])=O)=CC=1)([O-])=O>O1CCCC1.O>[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C@@H:23]2[CH2:27][C@H:26]([S:28][C:29]3[C@H:30]([CH3:53])[C@@H:31]4[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]4[C:33]=3[C:34]([OH:36])=[O:35])[CH2:25][NH:24]2)=[O:22])[CH2:17][C@@H:16]1[CH3:67])(=[NH:12])[CH3:14]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C[C@@H]1C
Solvent: O
Solvent: C1CCOC1
Product: CC(=N)N1CCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)C[C@@H]1C
Yield: 33.4 %

Procedure:
85 mg of 4-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-2-[(3S)-4-(N-4- nitrobenzyloxycarbonylacetimidoyl)-3-methylpiperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 4.1 ml of a 2:1 by volume mixture of tetrahydrofuran and water, and were hydrogenated by bubbling hydrogen through the solution at room temperature for 2 hours in the presence of 210 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 1(b), to give 14 mg of the title compound as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:22](O)[CH2:23][OH:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[O:10][CH2:22][CH2:23][O:24][CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1ccnc(Cl)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1cc(C2COCCO2)ccn1

Procedure:
A mixture of 21.3 g. (0.137 mole) of 1-(2-chloro-4-pyridyl)ethanone and 0.5 g. of p-toluenesulfonic acid in 40 ml. of ethylene glycol and 300 ml. of toluene was placed in a flask fitted with a Dean-Stark trap and condenser, and was heated at reflux temperature for 16 hours. The mixture was cooled and concentrated in vacuo to give an oil which was purified by distillation under reduced pressure, 23.6 g. (86%), b.p. 65° C. (0.05 torr).
Reaction SMILES: [B:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[O:5]1)([OH:3])[OH:2].[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:6](=[O:7])[O:5][CH:4]2[B:1]([OH:2])[OH:3])([O-:16])=[O:15]
Reactant: O=C1OC(B(O)O)c2ccccc21
Reactant: O=[N+]([O-])O
Product: O=C1OC(B(O)O)c2cc([N+](=O)[O-])ccc21
Yield: 71 %

Procedure:
Boronophthalide (2.86 g, 21.4 mmol) is added to 18.6 mL of chilled, fuming nitric acid (at 45° C.) in portions over 4 minutes with stirring. The reaction is quenched with ice and water (40 g and 60 mL), then the resulting pale yellow solid is collected on a Büchner filter and washed with 75 mL of water. Drying the solid in vacuo over P2O5 gives 2.72 g (15.2 mmol, 71.0%) 5-Nitroboronophthalide as a pale yellow solid (m.p. 178-179° C.).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[OH-].[K+].[CH3:18][C:19]([CH3:21])=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[C:19]([CH3:21])[CH3:18])[C:4]=2[CH:3]=1
Reactant: CC(C)=O
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Yield: 13 %

Procedure:
To a mixture of solid 2,7-dibromo-9H-fluorene (1 g, 3.1 mmol) and solid potassium hydroxide (freshly ground, 530 mg, 9.4 mmol) was added acetone (15 mL). The reaction immediately turns dark. After 3 hours the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (MgSO4) and concentrated to a dark blue-green oil. This oil was dissolved in dichloromethane (10 mL) and formic acid (˜10 drops) was added until the solution was bright orange. After concentration, the resulting residue was purified by flash column chromatography to yield 2,7-dibromo-9-(propan-2-ylidene)-9H-fluorene (145 mg, 13%) as an orange solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:25][C:24]4[CH2:23][CH2:22][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][C:19]=4[C:17]=3[CH:18]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:25][C:24]4[CH2:23][CH2:22][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][C:19]=4[C:17]=3[CH:18]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4ccc([N+](=O)[O-])cc4)cc3c2C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4ccc(N)cc4)cc3c2C1
Yield: 88.7 %

Procedure:
To a solution of product from step A (96 mg, 0.20 mmol) in ethanol (4.0 mL) and water (2.0 mL) was added iron powder (57 mg, 1.02 mmol) and ammonium chloride (12 mg, 0.22 mmol). After refluxing for 3 h, the reaction mixture was filtered through a bed of celite and the celite bed washed repeatedly with ethyl acetate. The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude product which was purified by flash column chromatography (SiO2, 3:2 hexanes/ethyl acetate) to give the product tert-butyl 8-(4-aminophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (76 mg, 87%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.22-8.19 (m, 1H), 7.88 (dd, J=8.7, 1.8 Hz, 1H), 7.81-7.75 (m, 2H), 7.67 (d, J=8.4 Hz, 1H), 6.97-6.91 (m, 2H), 4.48 (s, 2H), 3.54-3.52 (m, 2H), 3.23-3.16 (m, 2H), 1.55 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[C:8]1(=O)[CH2:11][CH2:10][CH2:9]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH:8]1([NH:7][C:4]2[NH:3][C:2]([CH3:1])=[N:6][N:5]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCC1
Reactant: Cc1nnc(N)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nnc(NC2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
To a solution (30 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (2.5 g) and cyclobutanone (2.1 g) in acetic acid was added sodium cyanoborohydride (8.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (2.4 g, 61%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].Cl.N[C:13]([O:20]CC)=[CH:14][C:15]([O:17][CH2:18][CH3:19])=O.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:18]([O:17][C:15]1[CH2:14][C:13](=[O:20])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[N:10]=1)[CH3:19]
Reactant: NNc1ccccc1F
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC1=NN(c2ccccc2F)C(=O)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(2-Fluorophenyl)hydrazine hydrochloride (1.00 g, 6.15 mmol) was suspended in ethanol (10 mL), treated with ethyl 3-amino-3-ethoxyacrylate hydrochloride (1.20 g, 6.15 mmol, 1.00 equiv), and placed into a preheated oil bath at 70° C. for 5 hours. The mixture was cooled to ambient temperature, poured into saturated aqueous sodium bicarbonate (100 mL), and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (100:0 to 0:100 hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1.C[Sn](C)(C)[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[OH-].[Na+]>C1(C)C(C)=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:29]1[CH:30]=[CH:31][C:26]([C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]4[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]4)[N:8]=3)=[CH:4][CH:3]=2)=[CH:27][CH:28]=1
Reactant: C[Sn](C)(C)c1ccncc1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)s3)n2)CC(C)(C)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC1(C)CC(Nc2nccc(-c3ccc(-c4ccncc4)s3)n2)CC(C)(C)N1
Temperature: 120 °C

Procedure:
[4-(5-Bromo-thiophen-2-yl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (Step C of Example 5, 100 mg, 0.253 mmol), 4-trimethylstannylpyridine (186 mg, 0.506 mol) and PdCl2(PPh3)2 (18 mg, 0.025 mmol) were dissolved in xylene (5 ml) and heated to 120° C. for 30 minutes. The reaction mixture was poured on 1N-NaOH and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, evaporated to dryness and purified via preparative HPLC to give the title compound as yellow crystals. Yield: 23 mg (23%)
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[C:9]2[C:14]([OH:15])=[C:13]([O:16][CH3:17])[C:12]([CH3:18])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(C)C=CC=CC=1>O1CCCC1>[CH2:22]([O:15][C:14]1[C:9]([C:8]([NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=2)=[O:19])=[CH:10][N:11]=[C:12]([CH3:18])[C:13]=1[O:16][CH3:17])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCc1ccccc1
Reactant: COc1c(C)ncc(C(=O)NCc2ccc(F)cc2)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1c(C)ncc(C(=O)NCc2ccc(F)cc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
To a solution of the compound 22 (100 g, 344 mmol), benzyl alcohol (46 ml, 447 mmol), and tributylphosphine (128 ml, 516 mmol) in tetrahydrofuran (1000 ml) was added a 40% diisopropyl azodicarboxylate-toluene solution (280 ml, 516 mmol) under ice-cooling over 30 minutes. After stirred for 30 minutes under ice-cooling, a temperature was raised to room temperature, followed by stirring for 2 hours. The solvent was distilled off under reduced pressure, to the residue were added toluene (100 ml) and hexane (2000 ml), and precipitated crystals were filtered. The solvent was distilled off under reduced pressure, to the residue were added diethyl ether (200 ml) and hexane (2000 ml), and precipitated crystals were filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). 4-Benzyloxy-N-(4-fluorobenzyl)-5-methoxy-6-methylnicotinamide 23 (68.5 g, 52%) was obtained as a colorless crystal.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:18]=[C:17]([C:19]4[N:23]([CH:24]([CH3:26])[CH3:25])[C:22]([CH3:27])=[N:21][CH:20]=4)[C:16]([F:28])=[CH:15][N:14]=3)=[CH:8][CH:7]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[F:28][C:16]1[C:17]([C:19]2[N:23]([CH:24]([CH3:25])[CH3:26])[C:22]([CH3:27])=[N:21][CH:20]=2)=[N:18][C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([N:4]3[CH2:3][CH:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:5]3)=[CH:11][CH:10]=2)=[N:14][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC(N)C4)cc3)ncc2F)n1C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC(NS(C)(=O)=O)C4)cc3)ncc2F)n1C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of N-[4-(3-aminoazetidin-1-yl)phenyl]-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (Example 140; 110 mg, 0.29 mM) and triethylamine (44 μl, 0.317 mM) in dry DCM (4.0 ml), methanesulphonyl chloride (25 μl, 0.317 mM) was added. The reaction was stirred at room temperature under nitrogen for 24 hours. The reaction was filtered and the filtered solid washed with DCM. This solid which was pure product was retained. The filtrate was taken and more DCM added. The solution was washed in turn with water (twice), saturated sodium chloride and then dried with anhydrous sodium sulphate, filtered and evaporated. The product so obtained was combined with the 1st batch of product and both were triturated with ether, filtered, washed with ether and dried to give the title compound as a yellow solid. NMR 1.4 (d, 6H), 2.6 (s, 3H), 2.9 (s, 3H), 3.55 (t, 2H), 4.13 (t, 2H), 4.25 (m, 1H), 5.37 (m, 1H), 6.4 (d, 2H), 7.33 (d, 2H), 7.58 (d, 1H), 7.75 (d, 1H), 8.5 (d, 1H), 9.22 (s, 1H); m/z 460.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[O:45]1[CH2:50][CH2:49][CH:48]([CH2:51][NH2:52])[CH2:47][CH2:46]1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:52][CH2:51][CH:48]3[CH2:49][CH2:50][O:45][CH2:46][CH2:47]3)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Reactant: NCC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)ccn1
Yield: 81.7 %

Procedure:
Combined 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid (30 mg, 0.096 mmol), EDCI (27.6 mg, 0.144 mmol), HOBT (19.47 mg, 0.144 mmol), and DMF (961 μl), then added (tetrahydro-2H-pyran-4-yl)methanamine (17.66 μl, 0.144 mmol) and Hunig's base (68.3 μl, 0.384 mmol) and stirred at room temperature overnight. The reaction mixture was purified via preparative HPLC to give the title compound (32.1 mg, 82%) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ ppm 1.35 (qd, J=12.38, 4.55 Hz, 2H) 1.71 (d, J=12.88 Hz, 2H) 1.84-1.99 (m, 1H) 3.42 (td, J=11.68, 1.64 Hz, 2H) 3.95 (d, J=3.28 Hz, 1H) 3.98 (s, 3H) 4.19 (s, 3H) 7.76 (d, J=6.57 Hz, 1H) 7.84 (s, 1H) 8.03 (d, J=6.57 Hz, 1H) 8.28-8.47 (m, 2H) 8.55 (br. s., 1H) 8.85 (br. s., 1H). MS m/z [M+H]+410.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[C:5]([F:11])=[CH:4][N:3]=1.[CH3:12][Mg]Br.C(OCC)C>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])([CH3:12])[CH3:9])[C:5]([F:11])=[CH:4][N:3]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1nc(Cl)ncc1F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1nc(Cl)ncc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
A stirred, −78° C. solution of 1-(2-chloro-5-fluoro-pyrimidin-4-yl)ethanone (10.06 g, 57.6 mmol) in tetrahydrofuran (100 mL) under nitrogen is reacted with a 3 M solution of methyl magnesium bromide in diethyl ether (124 mL, 72.04 mmol) and the resulting mixture is stirred at −78° C. for 20 minutes. The reaction is quenched with aqueous saturated ammonium chloride and the mixture is warmed to room temperature. The reaction mixture is extracted three times with ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated under vacuum. The crude product is purified over silica gel with a 30 minute, 5% to 100% ethyl acetate in hexanes gradient, to give the title compound (7.06 g, 64%). ES/MS (m/e): (35Cl/37Cl) 191/193 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si]([C:29]#[N:30])(C)C.[Sn](Cl)(Cl)(Cl)Cl>CCCCC.C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:29]#[N:30])=[O:7])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCCCC
Solvent: ClCCl
Product: N#CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
4-Fluorobenzoyl cyanide was prepared according to the general procedure reported by G. A. Olah et al. [supra]. Under dry conditions, 1.829 g of 4-fluorobenzoyl chloride (98%, Aldrich) (11.54 mmol), 30 mL of methylene chloride, freshly distilled from phosphorus pentoxide under nitrogen, and 1.8 mL of trimethylsilyl cyanide (13 mmol) were added to a 100-mL round bottom flask. To this solution 0.29 mL of tin (IV) chloride (2.5 mmol) was added. On addition of the tin (IV) chloride, the color of the solution changed from clear to dark yellow and within 5 min the color of the solution was dark brown. The reaction mixture was stirred for 2 hr at room temperature, then quenched with 90 mL of ice-cold water, and finally extracted with two 90-mL portions of methylene chloride. The methylene chloride extracts were combined, washed with two 90-mL portions of ice-cold water, dried with MgSO4, and filtered. The methylene chloride was removed by rotary evaporation. The dark brown residue which resulted was stirred with pentane. The pentane solution was decanted and the pentane removed by rotary evaporation to yield 0.911 g of 4-fluorobenzoyl cyanide as a yellow oil. The product was further purified by Kugelrohr vacuum distillation which afforded 0.666 g (39%) of 4-fluorobenzoyl cyanide as a colorless oil that solidified on standing in the freezer: IR (CCl4) (partial) 2220, 1685, 1600, 1505, 1410 cm-1.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([SH:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=O.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)#[N:16]>N1C=CC=CC=1>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[S:12][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:13])[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[N:16]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1S
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: O=c1nc(-c2ccccn2)sc2cc(C(F)(F)F)ccc12
Yield: 56 %

Procedure:
A mixture of 4-trifluoromethylthiosalicylic acid (2.5 g, 11 mmol), 2-cyanopyridine (1.2 g, 11 mmol) and pyridine (10 ml) was refluxed for 10 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from tetrahydrofuran-hexane to give the titled compound (1.9 g, 54%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[O:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].[Cl-].[NH4+]>C(Cl)(Cl)Cl>[CH3:26][S:27]([O:14][CH2:13][CH2:12][O:11][C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:29])=[O:28]
Reactant: OCCOc1ccccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OCCOc1ccccc1OCc1ccccc1
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of 2-(2-benzyloxyphenoxy)ethanol (3.07 g, 12.6 mmol) and triethylamine (2.63 ml, 18.8 mmol) in chloroform (30 ml) was added methanesulfonyl chloride (1.12 ml, 14.4 mmol) under ice-cooling, and the mixture was stirred for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue and the precipitated solid was collected by filtration and washed with hexane. The obtained solid was dried in vacuo to give 2-(2-benzyloxyphenoxy)ethyl methanesulfonate (3.77 g, yield 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:14][CH2:15][CH3:16])(OCC)[CH2:9][CH3:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[O:23](C(C(F)(F)F)=O)[C:24]([C:26]([F:29])([F:28])[F:27])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:14][CH2:15][CH3:16])=[C:9]([CH3:10])[C:24](=[O:23])[C:26]([F:29])([F:28])[F:27])=[CH:6][CH:7]=1
Reactant: CCOC(CC)(OCC)c1ccc(Cl)cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=C(C)C(=O)C(F)(F)F)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A solution of 2.0 g of 1-chloro-4-(1,1-diethoxypropyl)benzene and 2.5 mL of CH2Cl2 was treated with 1.45 mL of pyridine. The solution was cooled to 0° C. and treated with 5.5 mL of (CF3CO)2O in 2.5 mL of CH2Cl2. After heating overnight at reflux, the reaction mixture was cooled, diluted with CH2Cl2 and 12 mL of ice cold water was added. The organic layer was seperated and washed with 20 mL of 1N HCl, followed by a washing with 20 mL, of 10% Na2 CO3 and two washings with 20 mL of water. The organic layer was dried over Na2SO4 and concd in vacuo to yield 1.69 g of a dark brown oil. Chromatographic purification (silica, 10% ethyl acetate in hexanes) yielded 1.0 g of a yellow oil. Bulb to bulb distillation gave 0.45 g of a very pure light yellow oil: μ (23,D) 1.5137; major geometric isomer: 1HNMR (CDCl3) δ1.22 (t, 3H, 7.0Hz), 1.70 (s, 3H), 3.64 (q, 2H, 7.0 Hz), 7.30 (d, 2H, 8.3 Hz), 7.46 (d, 2H, 8.4 Hz). 19FNMR (CDCl3) δ-74.68 (CF3). Anal. Calcd for C13H12 O2F3Cl: C, 53.35; H, 4.13. Found: C, 53.44; H, 4.10.
Reaction SMILES: ClCCl.[OH:4][C:5]([CH3:14])([CH3:13])[C:6]#[C:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].ClS([N:19]=[C:20]=[O:21])(=O)=O>O>[C:20]([O:4][C:5]([CH3:13])([CH3:14])[C:6]#[C:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:21])[NH2:19]
Reactant: CCOC(=O)C#CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C#CC(C)(C)OC(N)=O
Yield: 33.6 %

Procedure:
To 100 ml of a dichloromethane solution containing 4.9 g (31.4 millimoles) of ethyl 4-hydroxy-4-methyl-2-pentynoate, 3 ml (34.5 millimoles) of chlorosulfonyl isocyanate was added at a temperature of -10° C. The mixture was reacted for 30 minutes at -10° C. under stirring. The reaction mixture was returned to room temperature, and 20 ml of water was added thereto. The mixture was stirred for 15 minutes for hydrolysis treatment. The dichloromethane phase was separated by phase separation, washed with a 10% barium chloride solution and water successively, dried over sodium sulfate and then concentrated under reduced pressure, whereby 2.1 g (yield: 33%) of ethyl 4-carbamoyloxy-4-methyl-2-pentynoate in crystal form was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].C[Mg]Cl.[CH2:15]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[C:30](Cl)=[O:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:15]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[C:30](=[O:31])[CH:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])[C:8](=[O:9])[CH3:10])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)C1CCCN1C(=O)OCc1ccccc1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)C(C(=O)OC(C)(C)C)C(=O)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
A solution of tert-butylacetoacetate (7.90 g, 50.0 mmol) in anhydrous THF (50 mL) was cooled to 4° C. (ice-water bath) prior to dropwise addition of methylmagnesium chloride (16.3 mL of a 3.00M solution in THF, 50.0 mmol) at such a rate that the temperature did not exceed 10° C. After the addition was complete the cooling bath was removed. When the temperature reached 15° C., 2-chlorocarbonyl-pyrrolidine-1-carboxylic acid benzyl ester (6.60 g, 25.0 mmol) was added dropwise over 1 h then warmed to rt and stirred for 12 h. The reaction was quenched with saturated aqueous NH4Cl (30 mL). The organic layer was separated from the solid residues and concentrated under vacuum to give 9.74 g (quant.) of 2-(2-tert-butoxycarbonyl-3-oxo-butyryl)-pyrrolidine-1-carboxylic acid benzyl ester as a yellow oil. The product was used directly in the subsequent step without further purification.