Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[NH:31]1CCC[C@H:32]1C(O)=O.C(=O)([O-])[O-].[K+].[K+].Cl.CN.[OH-].[NH4+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH:31][CH3:32])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: CN
Agent: Cl
Solvent: CS(C)=O
Product: CNc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12

Procedure:
6-Chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (Intermediate 1C; 6.08 g, 11.65 mmol), proline (0.42 g, 3.65 mmol), copper(I) iodide (0.24 g, 1.260 mmol), potassium carbonate (9.83 g, 71.1 mmol), and methylamine hydrochloride (3.26 g, 48.3 mmol) were stirred in DMSO (45 mL) at 70° C. for 24 h. Room temperature was attained, ammonium hydroxide was added, and the products extracted into DCM (×2). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (6-50% EtOAc-hexanes) gave 6-chloro-N-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine MS ESI calc'd. For C26H21ClN4 [M+1]+ 425. found 425.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(NC(C)C)(C)C.[Li].[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>O1CCCC1.CCCCCC.O1CCCC1>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)C(=O)Cl
Reactant: CCCCCCc1ccc(CC(=O)OCC)cc1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCc1ccc(C(C(=O)OCC)C(=O)C(C)C)cc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
6.0 g (24 mmol) of ethyl 2-(4-hexylphenyl)acetate was dissolved in 130 mL of dry tetrahydrofuran under a nitrogen atmosphere and cooled to −60° C. After addition of 31.8 mL (36.2 mmol) of 1.14 M solution of lithiumdiisopropylamine in hexane/tetrahydrofuran, the solution was warmed to 0° C. and stirred for 1 hours. The reactuion solution was cooled to −60° C. again and stirred with 3.6 g (34 mmol) of isobutyryl chloride at −60° C. to room temperature for 15 hours. The reaction was quenched with saturated aqueous sodium hydrogen carbonate (150 ml), and the reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate:hexane (0:100 to 1:9) as the eluent to give 5.39 g of the desired product as a pale yellw oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(=O)N[CH:34](C(N1CCCC1C1NC(C2C=CC(Br)=CC=2)=CN=1)=O)[CH:35](C)C>>[CH3:1][O:2][C:3](=[O:29])[NH:4][CH:5]([C:9]([N:11]1[CH:12]([C:16]2[NH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[CH2:13][C:14]2([CH2:35][CH2:34]2)[CH2:15]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Product: C#Cc1ccc(-c2cnc(C3CC4(CC4)CN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1

Procedure:
Title compound was prepared according to the method employed to prepare (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester from (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example AY), substituting (1-{6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:9][C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[C:12]([Cl:19])[C:11]=1[Cl:20])[CH2:5][C:6]([OH:8])=[O:7])[CH3:3].O.O.[Sn](Cl)(Cl)(Cl)Cl.NCC(O)=O.[Sn]>Cl>[CH2:2]([N:4]([CH2:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([Cl:19])[C:11]=1[Cl:20])[CH2:5][C:6]([OH:8])=[O:7])[CH3:3]
Reactant: CCN(CC(=O)O)Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: NCC(=O)O
Solvent: O
Product: CCN(CC(=O)O)Cc1c(N)ccc(Cl)c1Cl
Temperature: 45 °C
Yield: 58 %

Procedure:
A suspension of 30 g of ethyl N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride (compound VI) in 120 mL of concentrated hydrochloric acid was prepared. Separately, a mixture of tin chloride dihydrate (88.6 g) in 60 mL of hydrochloric acid is prepared. The glycine solution is slowly added to the tin solution and the resulting reaction mixture heated for 2 hours at 40-50° C. The solids are filtered, and the filter cake dissolved in water and methylene chloride. The pH of this solution is adjusted to 12.5 with 50% NaOH. The organic phase is separated and the aqueous phase extracted with methylene chloride. The combined organic phases are washed with water, and dried azeotropically. The solution is concentrated, isopropanol and heptane are added, and the solution cooled to −20 to −30° C. The precipated solids are collected by filtration. The crude product is recrystallized from heptane to give compound I in 58 to 67% yield.
Reaction SMILES: [NH:1]([C:35]([CH3:37])=[O:36])[C@@H:2]([C:18]([N:20]1[CH2:34][CH2:33][CH2:32][C@@H:21]1[C:22]([O:24]CC1C=CC=CC=1)=[O:23])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[OH-].[Na+].C(OC(C)C)(C)C.Cl>ClCCl.CO>[NH:1]([C:35]([CH3:37])=[O:36])[C@@H:2]([C:18]([N:20]1[CH2:34][CH2:33][CH2:32][C@@H:21]1[C:22]([OH:24])=[O:23])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: CC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: CO
Product: CC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
The Ac-D-Lys(Z)-D-Pro-OBzl compound obtained at the previous steps (in theory: 230 mmol) is mixed with 313 ml of methanol, added with 313 ml of 1N NaOH (313 mmol, 1.36 eq), and stirred overnight at room temperature. The reaction completion is CCM controlled. Thereafter, diisopropyl ether is added (313 ml, 11 vol.), the medium is decanted and the aqueous phase is extracted again three times with 3×150 ml of diisopropyl ether. The aqueous phase is then poured onto a blend of 540 ml of dichloromethane and 70 ml of aqueous 4N HCl (1.2 eq). The blend is stirred for 15 minutes and decanted. The separated organic phase is washed with water followed by a NaCl saturated aqueous solution (110 ml, 4 vol. each time). The organic phase is dried on Na2SO4 and vacuum concentrated (40° C. max, 50 mbar max.). The thus obtained product 94.25 g has the form of a foam (yield=98% calculated based on the involved Boc-D-Lys(Z)-OH).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1.ClCCl>N1C=CC=CC=1>[CH3:16][C:17]1[CH:21]=[C:20]([NH:22][S:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:15])([F:14])[F:1])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 10 %

Procedure:
To a stirring mixture of 4-(trifluoromethoxy)benzene-1-sulfonyl chloride (0.060 g, 0.23 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.050 g, 0.22 mmol) in pyridine (1.0 mL) was heated at 80° C. for 1 h. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 2-10% methanol in dichloromethane) and purification by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.010 g, 0.022 mmol, 10%). 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J=4.0 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.71 (s, 1H), 7.69 (s, 1H), 7.56 (t, J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.21-7.17 (m, 4H), 6.12 (s, 1H), 2.34 (s, 3H); MS: (ES) m/z calculated for C20H16F3N4O3S [M+H]+ 449.1. found 449.7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH:7]=1.Br[C:14]1[N:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][CH:15]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>CN(C=O)C.[Pd](Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([C:14]3[N:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][CH:15]=3)=[CH:11][N:12]=2)[CH:5]=[N:4][CH:3]=1
Reactant: N#Cc1cccc(Br)n1
Reactant: Fc1cncc(-c2nccs2)c1
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc(-c2cnc(-c3cncc(F)c3)s2)n1
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
Under argon, 3-fluoro-5-(1,3-thiazol-2-yl)pyridine (0.99 g, 5.47 mmol) and 6-bromopyridin-2-carbonitrile (1.0 g, 5.47 mmol) were initially charged in DMF (15 ml). After 10 min, at room temperature, tris(2-methylphenyl)phosphine (0.13 g, 0.23 mmol) and palladium(II) chloride (0.1 g, 0.55 mmol) were added. The reaction mixture was stirred at 130° C. for 14 h. After cooling, water and ethyl acetate were added and the precipitated product was filtered off with suction. The organic phase of the filtrate was removed and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and the solvent was removed under reduced pressure. The residue was stirred with dichloromethane and filtered off with suction. This gave a total of 0.94 g (61% of theory) of 6-[2-(5-fluoropyridin-3-yl)-1,3-thiazol-5-yl]pyridine-2-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CCC3(CC2)OCCO3)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: O=C1CCC(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
8-(4-fluor-phenyl)-1,4-dioxaspiro[4.5]decane (2 mmol) is dissolved in dioxane (6.5 ml) and treated with 3 ml 50% aqueous sulphuric acid accompanied by stirring at room temperature for 5 hours. After dilution with water (12 ml) extraction is carried out twice with dichloromethane. The raw title compound is obtained from the combined organic phases after drying over sodium sulphate and evaporating-off of the solvent in a vacuum (Tetrahedron 1998, 54, 15509-15524): tR 3.44 min (LC-1); ESI-MS(+): m/z 193.29 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:21][CH2:20][CH2:19][C@H:18]([N:22]([CH2:29][C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)[C:23]2[N:24]=[N:25][N:26]([CH3:28])[N:27]=2)[C:17]2[CH:44]=[C:45]([CH2:52][CH3:53])[C:46]([C:48]([F:51])([F:50])[F:49])=[CH:47][C:16]1=2)=O)(C)(C)C>ClCCl>[F:42][C:40]([F:41])([F:43])[C:32]1[CH:31]=[C:30]([CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=1)[CH2:29][N:22]([C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1)[C@H:18]1[CH2:19][CH2:20][CH2:21][NH:15][C:16]2[CH:47]=[C:46]([C:48]([F:49])([F:50])[F:51])[C:45]([CH2:52][CH3:53])=[CH:44][C:17]1=2
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.9 %

Procedure:
Add trifluoroacetic acid (1 mL) to a solution of (S)-5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid tert-butyl ester (2.04 g, 3.13 mmol) in dichloromethane (1 mL). Stir for 30 minutes at room temperature. Dilute the mixture with dichloromethane (40 mL) and wash with saturated aqueous sodium bicarbonate solution (40 mL). Dry organic layer over anhydrous sodium sulfate and filter. Remove the solvent under reduced pressure. Purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0-30%), to provide the title compound (0.318 g, 98%). MS (ES+): 567 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[C:11]4[CH:17]=[CH:18][CH:19]=[CH:20][C:10]4=[CH:9][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([OH:21])[CH:3]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>CC(C)=O>[O:26]1[CH2:25][CH:24]1[CH2:22][O:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[C:11]4[CH:17]=[CH:18][CH:19]=[CH:20][C:10]4=[CH:9][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([O:21][CH2:22][CH:24]2[CH2:25][O:26]2)[CH:3]=1
Reactant: ClCC1CO1
Reactant: O=c1c2cc3ccccc3cc2oc2cc(O)cc(O)c12
Solvent: CC(C)=O
Product: O=c1c2cc3ccccc3cc2oc2cc(OCC3CO3)cc(OCC3CO3)c12
Temperature: 57.5 °C
Yield: 7.3 %

Procedure:
1,3-dihydroxy-12H-benzo[b]xanthen-12-one (0.15 g, 0.54 mmol) synthesized in Step 1 of Example 18, CS2CO3 (0.53 g, 1.62 mmol), and anhydrous acetone (30 mL) were charged to a dry round-bottom flask, and epichlorohydrin (0.25 g, 2.7 mmol) was added thereto with stirring using a syringe. The reaction mixture was stirred with reflux under a nitrogen atmosphere (55 to 60° C., overnight). Solid of the reaction mixture was filtered and removed, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:3 (v/v)) to give the title compound (15.3 mg, 21.8%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.Br[CH2:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([S:23][CH2:25][C:26]5[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=5)[C:29]#[N:30])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Reactant: N#Cc1cccc(CBr)c1
Product: COc1ccc(-c2coc3ccc(-c4nnc(SCc5cccc(C#N)c5)o4)cc23)cc1
Yield: 87 %

Procedure:
In the same manner as in Example 1 and using 5-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-(bromomethyl)benzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 87%) was obtained as colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][CH2:8][CH2:9][OH:10].F[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]>C(#N)CC>[OH:10][CH2:9][CH2:8][S:7][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: OCCS
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC#N
Product: O=Cc1ccccc1SCCO
Temperature: 85 °C

Procedure:
To a slurry of potassium carbonate (362 g, 2.62 moles) in propionitrile (1000 ml) under nitrogen, was added 2-mercaptoethanol (184 ml, 2.618 moles) as a solution in propionitrile (750 ml). 2-Fluorobenzaldehyde (250 g, 2.014 moles) was added as a solution in propionitrile (750 ml) and heated at 85° C. for 18 hours. The reaction was cooled to 20° C. and sequentially washed with water (1500 ml), 1M sodium hydroxide solution (500 ml) and water (1000 ml). The final solution was dried by azeotropic distillation to leave the title compound as a clear, yellow solution in propionitrile (4250 ml). A small sample was concentrated for yield calculation (348.7 g, 95%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:23][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: BrCC1CCCCC1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC3CCCCC3)CC1)O2

Procedure:
Compound 136 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (bromomethyl)cyclohexane and conditions outlined in procedure V. LCMS: 398 [M+H]; Rt=1.03 min.
Reaction SMILES: CO[CH:3]([O:18]C)[CH2:4][NH:5][CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.S(=O)(=O)(O)O>>[CH2:11]1[C:12]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]2[CH2:6][NH:5][CH2:4][C:3](=[O:18])[N:9]2[CH2:10]1
Reactant: COC(CNCC(=O)NCCc1ccccc1)OC
Agent: O=S(=O)(O)O
Product: O=C1CNCC2c3ccccc3CCN12

Procedure:
Eur. J. Org. Chem. 2008, 895-913 describes a process comprising: a) reacting phenylethylamine with chloroacetyl chloride in presence of sodium bicarbonate to obtain 2-chloro-N-phenethylacetamide, b) treating 2-chloro-N-phenethylacetamide with aminoacetaldehyde dimethylacetal to give 2-[2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, c) making hydrochloride salt of 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, and d) cyclising using sulphuric acid to form praziquanamine (i.e.4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH3:12][Mg]I>>[CH3:12][C:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][CH:11]=1
Reactant: O=C1CCCc2ccccc21
Reactant: C[Mg]I
Product: CC1=CCCc2ccccc21
Yield: 68 %

Procedure:
α-Tetralone was reacted with methylmagnesium iodide as described in J. Org. Chem., 26, 4165 (1961), without isolation of the intermediate 1-methyl-1-tetralol, to give the desired product, after distillation, in 68% yield as a colorless oil, boiling point 55-57° C. at 0.8 mm Hg.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[C:14]([CH3:17])[S:15][CH:16]=1)[C:7]([O:9]CC)=[O:8].Cl>C(O)C>[CH3:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[C:14]([CH3:17])[S:15][CH:16]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(=NOC)c1csc(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C(C(=O)O)c1csc(C)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
1 N-Aqueous solution of sodium hydroxide (1.5 ml.) was added to a solution of ethyl 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (syn isomer) (0.3 g.) in ethanol (5 ml.) and the resulting mixture was stirred for 2 hours at 40° C. The reaction mixture was adjusted to pH 7.0 with 10% hydrochloric acid, concentrated under reduced pressure, adjusted to pH 1.5 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off to give crystalline substance of 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetic acid (syn isomer) (0.14 g.).
Reaction SMILES: [C:1]1(S(C(F)(F)F)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[K])(C)(C)C.C(OC)(=O)C1C=CC=CC=1.[F:30][C:31]([F:41])([F:40])C(C1C=CC=CC=1)=O.IC1C=CC=CC=1>[Cu](I)I>[F:30][C:31]([F:41])([F:40])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: O=S(=O)(c1ccccc1)C(F)(F)F
Agent: I[Cu]I
Agent: CC(C)(C)O[K]
Solvent: Ic1ccccc1
Solvent: COC(=O)c1ccccc1
Product: FC(F)(F)c1ccccc1
Yield: 26 %

Procedure:
The trifluoromethyl phenyl sulfone/tBuOK trifluoromethylation method can also be applied to other systems. For instance, methyl benzoate can be trifluoromethylated to generate 2,2,2-trifluoroacetophenone in 30% yield at about −50° C. to about −20° C. CF3Cu can be in situ generated with trifluoromethyl phenyl sulfone/tBuOK and copper iodide (CuI), and then further react with iodobenzene at 80° C. for 20 h to give α,α,α-trifluorotoluene in 26% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:17].[CH:18]1([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:20][CH2:19]1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CC#N.CN(C=O)C.O>[CH:18]1([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=4)[CH2:8][CH2:7][C:6]3=[O:17])[CH2:25][CH2:24]2)[CH2:19][CH2:20]1
Reactant: O=C1CCc2cc(F)c(F)cc2N1CCCCl
Reactant: C1CC(OCC2CC2)CCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C1CCc2cc(F)c(F)cc2N1CCCN1CCC(OCC2CC2)CC1
Temperature: 50 °C
Reaction time: 72 h
Yield: 81.5 %

Procedure:
A 4 ml vial was charged with 1-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (78 mg, 0.30 mmol), 4-cyclopropylmethoxypiperidine (145LH49) (42 mg, 0.27 mmol), NaI (75 mg, 0.50 mmol), and K2CO3 (69 mg, 0.50 mmol) in CH3CN/DMF (1 ml, 50:50). The reaction was shaken at 50° C. for 3 days and the reaction was poured into water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The oily residue was purified by ion-exchange column chromatography followed by flash column chromatography (SiO2; EtOAc) to yield the title compound as an oil (83 mg, 0.22 mmol, 81%). 1H NMR (CDCl3) δ 6.90 (dd, J=6.8, 12.0 Hz, 1H), 6.82-6.75 (m, 1H), 3.73 (t, J=7.2 Hz, 2H), 3.22-3.13 (m, 1H), 3.11 (d, J=6.8 Hz, 2H), 2.69-2.54 (m, 4H), 2.47-2.41 (m, 2H), 2.23-2.17 (m, 2H), 2.01-1.91 (m, 2H), 1.78-1.58 (m, 4H), 1.52-1.40 (m, 2H), 0.94-0.82 (m, 1H), 0.44-0.28 (m, 2H), 0.06 (−) 0.03 (m, 2H); 13C NMR (CDCl3) δ 166.4, 146.1 (dd, J=13, 243 Hz), 142.3 (dd, J=13, 243 Hz), 133.3 (dd, J=3, 8 Hz), 119.4 (dd, J=2, 5 Hz), 113.3 (d, J=18 Hz), 102.0 (d, J=22 Hz), 71.5 (br), 69.5, 52.2, 48.3, 38.0, 28.6, 28.2, 21.9, 21.7, 7.9, 0.0; HPLC-MS (ammonium acetate) [M+H]+=379.29.