Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(N(C)C)=O)=NC(N(C)C)=O.C([N:21]1[CH2:38][CH2:37][CH:25]2[N:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][C:34]=4[CH:24]2[CH2:23][CH2:22]1)[CH:29]([OH:36])[CH2:28][CH2:27]3)(=O)C1C=CC=CC=1.[C:39]1(O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(P(CCCC)CCCC)CCC>C1C=CC=CC=1>[O:36]([CH:29]1[C:30]2[C:35]3=[C:34]([C:24]4[CH2:23][CH2:22][NH:21][CH2:38][CH2:37][C:25]=4[N:26]3[CH2:27][CH2:28]1)[CH:33]=[CH:32][CH:31]=2)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(c1ccccc1)N1CCC2c3cccc4c3N(CCC4O)C2CC1
Reactant: Oc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: c1ccccc1
Product: c1ccc(OC2CCn3c4c(c5cccc2c53)CCNCC4)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 62.8 %

Procedure:
1,1′-Azobis(N,N-dimethylformamide) (0.34 g, 2.0 mmol) was added to a solution of 10-benzoyl-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-4-ol (0.45 g, 1.3 mmol), phenol (0.18 g, 1.9 mmol), and tributylphosphine (0.49 mL, 2.0 mmol) in dry benzene (4.0 mL) at room temperature under N2. The reaction mixture immediately congealed but resumed stirring upon heating to 60° C. After 5 h, the reaction was cooled to room temperature and filtered to remove white precipitate. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography with heptanes/EtOAc (gradient 3:1 to 3:2) to give 0.26 g (47%) of the title compound as a beige foam. 1H NMR (CDCl3) δ 7.52-7.38, 7.32, 7.11-6.95, 5.68, 4.21-3.90, 3.69, 3.21, 2.91, 2.63, 2.34; IR (drift) 1630, 1596, 1492, 1458, 1421, 1359, 1327, 1291, 1267, 1226, 1192, 786, 750, 706, 694 cm−1; MS (ESI) 423.3 (M++H).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][N:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:39]([O:44][CH2:45][CH2:46]O)(=[O:43])[C:40]([CH3:42])=[CH2:41].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:39]([O:44][CH2:45][CH2:46][O:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:9]2[O:10][C@H:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][N:13]=2)[C:2]=1[F:1])(=[O:43])[C:40]([CH3:42])=[CH2:41]
Reactant: C=C(C)C(=O)OCCO
Reactant: Oc1cccc(C2=NC[C@@H](c3ccccc3)O2)c1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCOc1cccc(C2=NC[C@@H](c3ccccc3)O2)c1F
Reaction time: 24 h
Yield: 85.5 %

Procedure:
To a solution of 4,5-dihydro-2-(2-fluoro-3-hydroxyphenyl)-5(R)-phenyloxazol e (0.97 g, 3.8 mmol), triphenylphosphine (1.0 g, 4.0 mmol) and 2-hydroxyethyl methacrylate (0.50 ml, 4.0 mmol) in THF (30 ml) was added dropwise a solution of diethyl azodicarboxylate (0.65 ml, 4.0 mmol) in THF (15 ml). After stirring for 1 day, volatiles were removed by evaporation. The residue was purified by column chromatography on silica gel eluting with hexane-ethyl acetate (2:1) to afford the title compound (1.2 g, 86%) as a pale yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[CH3:17]OC(OC)(C)C.Cl>CO.O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[CH2:9][C:10]([CH3:14])([CH3:15])[C:11]([O:13][CH3:17])=[O:12])=[CH:6][CH:7]=1
Reactant: COC(C)(C)OC
Reactant: CC(C)(CC(=O)c1ccc(Br)cc1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)CC(=O)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 22 h

Procedure:
To a solution of 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoic acid (8.33 g, 29.2 mmol) and 2,2-dimethoxypropane (3.95 g, 37.9 mmol) in methanol (100 mL) was added 1 M HCl in dioxane (2.0 mL). The reaction mixture was stirred at 50° C. for 22 h. The mixture was concentrated under reduced pressure. Toluene (2×60 mL) was added and the mixture concentrated again (2×) to afford methyl 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoate as an off-white, semi-solid (8.60 g, 99%). This material was used in the next step without further purification. LC-MS: ret. time 3.23 min; m/z 298.8 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.34 (s, 6H), 3.28 (s, 2H), 3.67 (s, 3H), 7.58 (d, 2H), 7.78 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[F:10][C:11]([F:29])([F:28])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:24]2([OH:27])[CH2:25][CH2:26][N:21]([C:18]3[CH:19]=[CH:20][C:15]4[N:16]([C:12]([C:11]([F:29])([F:28])[F:10])=[N:13][N:14]=4)[N:17]=3)[CH2:22][CH2:23]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: O=C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Solvent: C1CCOC1
Product: OC1(c2cccc(F)c2)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 18 %

Procedure:
3-Fluorophenylmagnesium bromide (1.0M in THF, 1.68 mL, 1.68 mmol) was added dropwise to 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-one (400 mg, 1.40 mmol) in THF (10 mL) cooled to 0° C. over a period of 10 minutes. The resulting mixture was stirred at 0° C. for 20 minutes, then quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate. The extract was washed with saturated brine, dried over MgSO4 and evaporated to a pale orange oil which was triturated with DCM to give a beige solid. The solid was filtered, washed with DCM and dried, then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-(3-fluorophenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (96 mg, 18%) as a colourless solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>CN(C)C=O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13]
Reactant: O=C1CCc2ccccc2N1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2ccccc2N1CCCCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
A suspension of sodium hydride (6.8 g, 60% dispersion in mineral oil) and dimethyl formamide (200 mL) was kept at 20–30° C. followed by the addition of a solution of 3,4-dihydroquinolin-2(1H)-one (25 g) in dimethyl formamide (100 mL). The resulting mixture was stirred at room temperature for 30 min followed by the addition of a solution of 1,4-dibromobutane (184 g) in dimethyl formamide (200 mL) at a temperature of 20–40° C. The reaction mixture was stirred at room temperature for 30 min and evaporated in vacuo. The remaining oil was poured into ice water and extracted with ethyl acetate. The combined organic phases were washed with water and brine, treated with charcoal, dried (MgSO4) and evaporated in vacuo. The remaining oil was purified by flash chromatography (eluent:ethyl acetate/heptane 1:1) giving the title compound as a red oil (36 g).
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[CH2:13]([C:21]1[CH:29]=[CH:28][C:24](C(O)=O)=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[C:1]([C@@H:3]([NH:5][C:6](=[O:12])[C:24]1[CH:23]=[CH:22][C:21]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:29][CH:28]=1)[CH3:4])#[N:2]
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Reactant: CCCCCCCCc1ccc(C(=O)O)cc1
Product: CCCCCCCCc1ccc(C(=O)N[C@@H](C)C#N)cc1
Yield: 42.9 %

Procedure:
General procedure D was used to deprotect 2.8 mmols of 4 and immediately couple to 2.8 mmols of 2 using general procedure F. The product was purified using column chromatography using a solvent system of ethyl acetate and hexanes (1:3, Rf=0.5) to yield 0.340 g (1.2 mmols) of the desired product. 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J=8.2, 2H), 7.23 (d, J=7.6, 2H), 6.75 (s, 1H), 5.27-5.06 (m, 1H), 2.71-2.55 (m, 2H), 1.64 (d, J=7.2, 2H), 1.61-1.53 (m, 1H), 1.35-1.13 (m, 10H), 0.87 (t, J=6.8, 3H). 13C NMR (126 MHz, CDCl3) δ 166.56, 147.99, 129.93, 128.81, 128.62, 127.18, 127.03, 119.40, 52.73, 48.54, 36.23, 35.86, 31.84, 31.22, 31.15, 29.41, 29.22, 22.64, 19.60, 18.71, 14.11.
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[N:6]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:7](=[O:30])[N:8]([CH:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10](=[O:23])[N:11]3[CH2:16][CH2:15][N:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[CH:44](=O)[CH2:45][CH3:46]>C1COCC1>[Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[N:6]([S:31]([C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)(=[O:33])=[O:32])[C:7](=[O:30])[N:8]([CH:9]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:10](=[O:23])[N:11]3[CH2:12][CH2:13][N:14]([CH:17]4[CH2:18][CH2:19][N:20]([CH2:44][CH2:45][CH3:46])[CH2:21][CH2:22]4)[CH2:15][CH2:16]3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCN(C4CCNCC4)CC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Reactant: CCC=O
Solvent: C1CCOC1
Product: CCCN1CCC(N2CCN(C(=O)C(c3ccccc3)n3c(=O)n(S(=O)(=O)c4ccc(OC)cc4)c4ccc(Cl)cc43)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 52 mg (0.08 mmol) of 5-chloro-1-(4-methoxybenzenesulfonyl)-3-[2-oxo-1-phenyl-2-(4-piperidin-4-ylpiperazin-1-yl)-ethyl]-1,3-dihydrobenzimidazol-2-one (Example 128) in 3 ml of THF was mixed with 5.32 mg (0.09 mmol) of propionaldehyde and 70 mg of MP-triacetoxyborohydrde resin (Argonaut, 2.55 mmol/g, 0.17 mmol) and shaken at room temperature overnight. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase gradient 8-11% methanol in dichloromethane). Yield: 33.2 mg (60%) of colorless solid
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].S(O)(C)(=O)=O.C1C(=O)N([Br:23])C(=O)C1>>[Br:23][C:7]1[C:6]([CH3:10])=[C:3]([C:2]([F:1])=[CH:9][CH:8]=1)[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(F)c1C#N
Agent: CS(=O)(=O)O
Product: Cc1c(Br)ccc(F)c1C#N
Temperature: 50 °C
Reaction time: 33 h

Procedure:
To a 3 L 3 Neck round bottomed flask equipped with overhead stirrer was charged 2-fluoro-6-methyl-benzonitrile (191.8 g., 1419 mmol) and MsOH (563 mL, 8516 mmol). NBS (265 g., 1490 mmol) was added portionwise to this stirred solution over 30 minutes, and the mixture was stirred at 50° C. for 33 hours. The reaction was poured into 1 L of ice, diluted with 700 mL 30% EtOAc/Hexanes, and agitated. The aqueous layer was cut, and the organics washed 2× with 1N NaOH and with water. The organics were dried over MgSO4, concentrated, then stored in a −10° C. freezer overnight. Precipitate formed over this time, and was filtered and washed with 5% EtOAc/Hexanes, providing a first crop of product. A second crop of precipitate provided additional 3-Bromo-6-fluoro-2-methyl-benzonitrile.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([Cl:12])=[C:7]([N+:13]([O-])=O)[CH:6]=1)(=[O:3])[CH3:2]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[C:1]([NH:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([Cl:12])=[C:7]([NH2:13])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(Cl)cc1F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(N)c(Cl)cc1F
Temperature: 90 °C
Yield: 60.4 %

Procedure:
Iron powder (31.9 g) were suspended in a 5% acetic acid solution (60 ml), and the suspension was heated to 90° C. A solution of 4-(N-acetylamino)-1-chloro-5-fluoro-2-nitrobenzene (13.3 g) in acetic acid (100 l ml) and ethyl acetate (70 ml) was dropwise added thereto, and the resultant mixture was refluxed at 80° C. for 2 hours. The reaction mixture was filtered by celite. The filtrate was extracted with ethyl acetate, and the extract was neutralized with a saturated sodium hydrogen carbonate solution. The organic layer was washed with water, dried and concentrated under reduced pressure to give 7.0 g of 4-(N-acetylamino)-2-amino-1-chloro-5-fluorobenzene. M.P., 140.5°-141.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>ClCCl>[CH2:19]([O:18][C:16]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
20 g of 4-aminophenol (Mw=109.13; 0.18324 mol) are suspended in 200 cm3 of anhydrous dichloromethane, under an inert atmosphere. The suspension is cooled to a temperature of 0° C. in a bath of ice and 16.4 cm3 of anhydrous pyridine (Mw=79.10; d=0.981; 0.2034 mol) are then added. 17.6 cm3 of ethyl chloroformate (Mw=108.53; d=1.13; 0.18324 mol) are then added dropwise so as to keep the mixture at a temperature below 10° C. The reaction mixture is kept stirring for two hours. The mixture is poured onto one litre of ice-cold water and then extracted with ethyl acetate. The organic phase is washed with water and then dried, filtered and evaporated under vacuum. After recrystallization from a heptane/ethyl acetate mixture, 21 g of a white powder are obtained, which corresponds to a yield of 63%. The melting point of the product obtained is 127.2° C. The 1H NMR spectrum and the elemental analysis are in accordance with the expected product.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:8](Cl)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[OH-].[NH4+:13]>>[Cl:1][C:2]1[S:3][C:4]([S:8]([NH2:13])(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(Cl)sc1S(=O)(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1nc(Cl)sc1S(N)(=O)=O
Yield: 88.2 %

Procedure:
Prepared by general procedure III from 2-Chloro-4-methyl-thiazole-5-sulfonyl chloride (1.0 g, 4 mmol,) and ammonium hydroxide (0.32 mL, 4 mmol) to give 2-Chloro-4-methyl-thiazole-5-sulfonic acid amide (0.75 g, 81%) as a white solid. MS (ISP) 213.0 [(M+H)+], 215.1[(M+2+H)+].
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)=[CH:3]1.[C:23](OC=C)(=[O:25])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(O)=O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CC(CC(C)C)=O>[C:23]([O:1][C@@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)=[CH:3]1)(=[O:25])[CH3:24]
Reactant: O=C1CC(O)C=C1Cc1cccc(OCc2ccccc2)c1
Reactant: C=COC(C)=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)CC(C)C
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1C=C(Cc2cccc(OCc3ccccc3)c2)C(=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
4-Hydroxy-2-(3-Benzyloxybenzyl)cyclopent-2-enone (2.1 kg, 7.14 mol) was dissolved in isobutyl methyl ketone (21 L), and vinyl acetate (4.2 kg, 51.16 mol) and Lipase derived from Pseudomonas cepacia (210 g) was added to the solution, and the mixture was stirred at room temperature for 1 day. The reaction mixture was filtered to remove Lipase and the filtrate was evaporated. The resulting residue was dissolved in PhCH3 (20 L), and triphenylphosphine (625 g, 2.38 mol) and AcOH (145 g, 2.41 mol) was added to the solution. Then diisopropylazodicarboxylate (413 g, 2.04 mol) was added to the mixture at 5° C. After the reaction was completed, the reaction mixture was filtered to remove the precipitate and the filtrate was evaporated. The residue was dissolved in EtOAc (5 L) and hexane (5 L) was added. The mixture was stirred at room t temperature overnight. The mixture was filtered to remove the precipitate and the filtrate was evaporated. The residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give the (R)-3-(3-benzyloxybenzyl)-4-oxocyclopent-2-enyl acetate as yellow oil: 1.8 kg (yield: 75%, 97% ee by HPLC using a chiral column)
Reaction SMILES: [C:1]([C:3]1[C:4]([OH:11])=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].[Br:12]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:12][C:7]1[C:8]([CH3:9])=[C:3]([C:1]#[N:2])[C:4]([OH:11])=[N:5][C:6]=1[CH3:10]
Reactant: Cc1cc(C)c(C#N)c(O)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(O)c(C#N)c(C)c1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.8 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 14.9 grams (0.10 mole) of 3-cyano-2-hydroxy-4,6-dimethylpyridine is cooled in an ice bath and a solution of 18.1 grams (0.10 mole) of N-bromosuccinimide in 50 mL of N,N-dimethylformamide is added dropwise during a 15 minute period. Upon completion of addition the reaction mixture is stirred at ambient temperature for about 72 hours. After this time, the reaction mixture is diluted to 1000 mL with water and filtered to collect a solid. The solid is dried under vacuum at about 60° C., yielding 22.2 grams of 5-bromo-3-cyano-2-hydroxy-4,6-dimethylpyridine, mp 254°-262° C. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][C:17]=1[C:27]([F:30])([F:29])[F:28]>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][C:17]=2[C:27]([F:28])([F:30])[F:29])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1
Reaction time: 0.33 h

Procedure:
To a solution of N-methylpiperazine (5.8 g, 57.9 mmol, 1.0 eq.) in tetrahydrofuran (225 ml) containing anhydrous finely ground potassium carbonate (10.4 g, 75.2 mmol, 1.3 eq.) is added a solution of ethyl 4-bromomethyl-3-trifluoromethylbenzoate (18.0 g, 57.9 mmol, 1.0 eq.) in tetrahydrofuran with vigorous mechanical stirring within 20 min. Stirring is continued at room temperature for 20 h. The obtained suspension is filtered, and the filtrate is evaporated to give a brown oil. The crude product is purified by medium pressure chromatography (290 g silica gel, gradient: TBME to EtOH/TBME 1:4 within 30 min, then 25% NH3/EtOH/TBME 1:19:80 for 60 min). The fractions containing the title compound are pooled and evaporated to afford a yellow oil: HPLC: tR=4.75 min (purity: >99%, gradient A), ESI-MS: 331.4 [MH]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([N:14]=[C:15](SC)[S:16][CH3:17])#[N:13]>CO>[C:12]([NH:14][C:15](=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[S:16][CH3:17])#[N:13]
Reactant: NCCSCc1ccccn1
Reactant: CSC(=NC#N)SC
Solvent: CO
Product: CSC(=NCCSCc1ccccn1)NC#N
Reaction time: 0.5 h

Procedure:
A solution of 2-[(2-pyridyl)methylthio]ethylamine (from the dihydrobromide, 20.0 g; 60.6 mmoles) and dimethyl cyanodithioimidocarbonate [prepared according to the procedure described in J. Org. Chem., 32, 1566 (1967)] (8.86 g; 60.6 mmoles) in methanol (150 ml) was stirred at ambient temperature under a positive pressure of nitrogen for 16 hours and then a reflux temperature for 0.5 hours to complete the reaction. The reaction mixture was evaporated under reduced pressure and the crude product was recrystallized from acetonitrile to give N-cyano-N'-{2-[(2-pyridyl)methylthio]ethyl}-S-methylisothiourea; mp 85°-86.5°.
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].N[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=[O:22])[C:10]([O:20][CH3:21])=[C:11]([O:18][CH3:19])[C:12]2=[O:17].C(O)(=O)C.N([O-])=O.[Na+].[ClH:31]>O>[Cl:31][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=[O:22])[C:10]([O:20][CH3:21])=[C:11]([O:18][CH3:19])[C:12]2=[O:17]
Reactant: COC1=C(OC)C(=O)c2c(N)cccc2C1=O
Reactant: Cl
Agent: O=N[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC1=C(OC)C(=O)c2c(Cl)cccc2C1=O
Temperature: -5 °C

Procedure:
A solution of sodium nitrate (0.69 g, 10 mmol) in water (5 ml) was added at 0°-5° C. to a solution of 5-amino-2,3-dimethoxy-1,4-naphthoquinone (1.17 g, 5 mmol) in 5:1 acetic acid:water (25 ml) containing concentrated hydrochloric acid (1.7 ml). A further quantity of sodium nitrite (0.69 g) was then added to the reaction mixture after cooling to -5° C., followed by a solution of cuprous chloride (0.6 g) in concentrated hydrochloric acid (5 ml). The mixture was allowed to warm to 22° C. and solid cuprous chloride was added portionwise until the mixture assumed a green color. Water was then added to the reaction mixture and the precipitated yellow solid filtered off, washed with water and recrystallized from methanol:water (2:1) giving 1.01 g of 5-chloro-2,3-dimethoxy-1,4-naphthoquinone, mp 120°-121° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:22])[CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:12].CS(C)=O>CCOCC>[CH2:11]([O:13][C:14](=[O:22])[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)[CH3:12]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CC1CCNCC1
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)CC1CCN(c2ccc(C(C)=O)cc2)CC1
Temperature: 150 °C

Procedure:
A microwave vial was charged with 4′-fluoroacetophenone (1.2 Ml, 10.4 mmol, 1.0 equiv) and 2-(piperidin-4-yl)-acetic acid ethyl ester (3.5 g, 20.7 mmol, 2.0 equiv) in 20 Ml DMSO. The homogeneous reaction was heated to 150° C. for 20 min. The cooled reaction was then diluted with ether and washed sequentially with saturated ammonium chloride, water, and brine. The organic extracts were then dried over sodium sulphate, filtered, and concentrated in vacuo. Purification by flash chromatography (10-40% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (t, J=7.07 Hz, 3H) 1.47 (d, J=12.13 Hz, 2H) 1.62 (br.s., 1H) 1.90 (d, J=12.63 Hz, 2H) 2.04-2.15 (m, J=11.18, 11.18, 7.45, 7.45, 3.79, 3.66 Hz, 1H) 2.33 (d, J=7.07 Hz, 2H) 2.57 (s, 3H) 2.97 (td, J=12.57, 2.15 Hz, 2H) 3.93 (d, J=12.88 Hz, 2H) 4.20 (q, J=7.07 Hz, 2H) 6.96 (d, J=6.82 Hz, 2H) 7.92 (d, J=9.09 Hz, 2H); (M+H)+290.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13]O)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.CS(Cl)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH2:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(CO)c1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C=C(C(=O)OC)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
Methyl 2-(4-chlorophenyl)-3-hydroxypropanoate (39.4 g, 184 mmol) was dissolved in DCM (500 mL) and treated with TEA (64.0 mL, 459 mmol). The solution was cooled to 0° C. The solution was then slowly treated with MsCl (15.6 mL, 202 mmol) and allowed to stir for 30 minutes. The solution was partitioned with 1N HCl solution, and the aqueous layer was extracted once into DCM. The combined organic layers were washed once more with 1N HCl solution, separated, washed with diluted NaHCO3 solution, and separated. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford an oil which was loaded onto a large fritted filter with a plug of silica gel and eluted with 9:1 hexane:ethyl acetate to give methyl 2-(4-chlorophenyl)acrylate as an oil (30.8 g, 85%).