Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=[O:2].Cl.C[N:7]1[C:11]2[CH2:12][CH2:13][CH:14]([C:16]([OH:18])=O)[CH2:15][C:10]=2[N:9]=[CH:8]1.[CH3:19][O:20][C:21]1[C:22]([NH2:27])=[CH:23][CH:24]=[CH:25][CH:26]=1.C(N(CC)CC)C>ClCCl>[OH2:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:16]([CH:14]1[CH2:13][CH2:12][C:11]2[N:7]=[CH:8][NH:9][C:10]=2[CH2:15]1)=[O:18]
Reactant: Cn1cnc2c1CCC(C(=O)O)C2
Reactant: O=S(Cl)Cl
Reactant: COc1ccccc1N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)C1CCc2nc[nH]c2C1
Product: O
Temperature: 90 °C
Reaction time: 21 h

Procedure:
Thionyl chloride, 10 ml, was added to 1.4 g (2.7 mmols) of 1-methyl-4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid hydrochloride (including NaCl) obtained in Reference Example 1 and the mixture was heated at 90° C. for 4 hours. After thionyl chloride was distilled off under reduced pressure, 10 ml of dichloromethane was added to the residue and at 0° to 4° C., 0.50 ml (4.4 mmols) of o-anisidine and 1.0 ml (7.2 mmols) of triethylamine were added to the mixture followed by stirring at room temperature for 21 hours. After 40 ml of dichloromethane was added to the reaction mixture, the mixture was washed with 1 N sodium hydroxide solution and then dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with dichloromethane methanol-ammonia water (10 : 1 : 0.1). The solvent was distilled off and the resulting crystals were recyrstallized from ethyl acetate to give 0.18 g of N-(2-methyoxyphenyl)-4,5,6,7-tetrahydrobenzimidazole -5-carboxamide hydrate.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Si](C=[N+]=[N-])(C)(C)[CH3:14].CCCCCC>C(Cl)Cl.CO>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:12])=[C:10]([F:11])[C:2]=1[F:1]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1ccc(C(=O)O)c(F)c1F
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(C)c(F)c1F
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 2,3-difluoro-4-methyl-benzoic acid (5.0 g, 29 mmol) in CH2Cl2 (20 mL) and MeOH (20 mL) is added 2.0 M TMSCHN2 in hexane (17.5 mL, 34.9 mmol) at 0° C. The reaction mixture is stirred for 1.0 h. The reaction mixture is concentrated to a residue and the residue is purified by flash chromatography to afford the title compound as an oil (5.7 g, 100%). LC-ES/MS m/e 208.3 (M+23).
Reaction SMILES: [CH:1](=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].[C:8]([O:11]C(=O)C)(=[O:10])[CH3:9].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH:1]([OH:7])=[CH:2][CH:3]=[CH:4][CH2:5][CH3:6].[C:8]([O-:11])(=[O:10])[CH3:9]
Reactant: CCC/C=C/C=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)[O-]
Product: CCC=CC=CO
Temperature: 80 °C

Procedure:
To a mixture of trans-2-hexenal (84.4 g; 0.86 mol) and acetic anhydride (102 g, 1 mol), 8 g (0.065 mol) of 4-dimethylaminopyridine and 105 g (1.04 mol) of triethylamine are added. The mixture is heated to 80° C. for two hours and then, after cooling at room temperature, 200 ml of chloroform is added. The organic layer is washed with two portions of 100 ml of ice-water and then with 30 ml of aqueous sodium bicarbonate. The chloroform layer is dried over MgSO4. Evaporation of the solvent under vacuum yields a residue which is distilled at 80° C./60 mmHg. Yield 106 g. N.M.R. and I.R. Spectrum confirm the assigned structure. The product is a mixture of four isomers containing more than 65% of the Δ-3,4-(E)-isomers.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:40][CH:41]=2)[CH2:31][CH2:30]1.C[Al](C)C>C(Cl)Cl.CO>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[CH:7]=[CH:8][C:9]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)=[O:3])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2cccnc12
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3ncccc23)c1F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 5-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid ethyl ester (Step 174.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 2 h at 80° C. Title compound: ESI-MS: 534.1 [M+H]+; tR=3.56 min (System 1); TLC: Rf=0.14 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16](Cl)=[O:17].C(N(CC)CC)C.O>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:16]([C:15]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([C:12]([F:11])([F:25])[F:24])[CH:14]=2)=[O:17])[C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2
Reactant: c1cc2c(cn1)NCCO2
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)N2CCOc3ccncc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 50 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (1.0 g, 7.34 mmol) and 3-trifluoromethyl-4-methoxy-benzoyl chloride (2.1 g, 8.80 mmol) were dissolved in dichloromethane. Triethylamine (2.0 ml, 14.68 mmol) was added thereto and then stirred at room temperature for 4 hours. To the reaction mixture, water was added to quench the reaction and the mixture was extracted with dichloromethane, and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN2CCCC2)no1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (126 mg, 0.25 mmol) and pyrrolidine (100 μl, 1.20 mmol) as starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([NH:9][C:10]2=O)[CH2:7]3)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([N:9]=[C:10]2[Cl:16])[CH2:7]3)=[CH:4][CH:3]=1
Reactant: O=C1NC2CC(C2)c2ccc(Br)cc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: ClC1=NC2CC(C2)c2ccc(Br)cc21
Temperature: 85 °C
Reaction time: 5 h
Yield: 108.6 %

Procedure:
Into a 5000-mL 3-necked round-bottom flask was placed 5-bromo-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6-trien-8-one (223 g, 884.55 mmol, 1.00 equiv), PhCH3 (3500 mL), PCl5 (560 g, 2.69 mol, 3.00 equiv), and DIPEA (275 g, 3.00 equiv). The resulting solution was stirred at 85° C. for 5 h and quenched by the addition of 300 g of DIPEA. The solids were filtered out and the filtrate was concentrated under vacuum to afford 260 g (crude) of 5-bromo-8-chloro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraene as a black oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23]C)=[O:22])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:26]1[S:27][C:28]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:29]=2[N:30]=1.Cl>C(O)CCC.O1CCOCC1.C(OCC)C>[F:38][C:35]([F:36])([F:37])[C:33]1[CH:32]=[CH:31][C:29]2[N:30]=[C:26]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]5[CH2:20][CH2:19][CH2:18][C@H:17]5[C:21]([OH:23])=[O:22])=[O:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[S:27][C:28]=2[CH:34]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: FC(F)(F)c1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCCCO
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(C(F)(F)F)cc4s3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
A mixture of methyl (1R,2R)-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylate (150 mg, 0.464 mmol) and 2-chloro-6-(trifluoromethyl)-1,3-benzothiazole(132 mg, 0.557 mmol) was diluted with n-butanol (3 mL) and treated with a catalytic amount of 4 M HCl in dioxane. The suspension was heated at 90° C. overnight. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel, eluting with a gradient from 9:1 to 3:2 hexanes/ethyl acetate. The product obtained was suspended in diethyl ether, and the resulting solid was collected by filtration and washed with additional diethyl ether and hexanes. LC-MS for the n-butyl ester: LC-MS m/z 567.3 (MH+), 4.67 min; 1H NMR (300 MHz, CDCl3) δ 8.14–8.10 (m, 3 H), 7.80–7.71 (m, 6 H), 7.62 (d, 2 H), 4.17–4.13 (m, 1 H), 4.09–4.04 (m,2 H), 3.51–3.41 (m, 1 H), 2.21–2.13 (m, 2 H), 1.97–1.90 (m, 1 H), 1.81–1.78 (m, 3 H), 1.58–1.51 (m, 2 H), 1.35–1.28 (m, 2 H),1.23–1.18 (t, 3 H), 0.88 (t, 2 H). The off-white solid was diluted with methanol (2 mL) and tetrahydrofuran (2 mL) and treated with 2 M aqueous sodium hydroxide solution (2 mL). The solution was stirred overnight at rt. The mixture was acidified by the addition of an excess of 2 M aqueous hydrochloric acid solution. The acidic solution was extracted with ethyl acetate. The organic phases were combined, dried (MgSO4), and concentrated under reduced pressure. The residue was suspended in methanol and the resulting solids were removed by filtration. The filtrate, which contained the product, was concentrated under reduced pressure to provide the title compound as a pale orange solid (30 mg, 13% overall yield). 1H NMR (tetrahydrofuran-d8) δ 10.85 (s, 1 H), 8.11–8.07 (m, 3 H), 7.96–7.91 (m, 2 H), 7.79–7.71 (m, 5 H), 7.63–7.59 (dd, 1 H), 4.18 (q, 1 H), 3.37 (q, 1 H), 2.2–1.77 (m, 6 H); LC-MS m/z 511.3 (MH+), retention time 4.27 minutes.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1([CH3:36])[C:18]2=[CH:19][C:20]3[N:21]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:22]4[C:27]([C:28]=3[CH:29]=[C:17]2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:20]1[CH:19]=[C:18]3[C:10]([CH3:36])([CH3:9])[C:11]4[C:16]([C:17]3=[CH:29][C:28]2=1)=[CH:15][CH:14]=[CH:13][CH:12]=4
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccccc4)c3cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1(C)c2ccccc2-c2cc3c4cc(Br)ccc4n(-c4ccccc4)c3cc21
Reaction time: 6 h

Procedure:
9.51 g (54 mmol) of N-bromosuccinimide are added over the course of 15 min to a solution of 19.3 g (54 mmol) of 12,12-dimethyl-10-phenyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene in 80 ml of chloroform at RT under a protective-gas atmosphere and with exclusion of light. The mixture is stirred for 6 h, 80 ml of sat. Na2CO3 soln. are subsequently added, and the organic phase is separated off and dried over Na2SO4. After removal of the solvent under reduced pressure, the residue is recrystallised, giving the product as a colourless solid in a yield of 20 g (45 mmol), 85%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[I-].[K+].II>C(O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([S:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5][NH:6]2
Reactant: Sc1ccccc1
Reactant: Brc1cccc2[nH]ccc12
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Brc1cccc2[nH]cc(Sc3ccccc3)c12
Temperature: 45 °C
Yield: 99.6 %

Procedure:
A stirred solution of 4-bromo-1H-indole (4.69 g, 23.9 mmol) in ethanol (110 mL) was added thiophenol (2.46 mL, 23.9 mmol). A solution of potassium iodide (3.97 g, 24 mmol) and iodine (6.07 g, 24 mmol) dissolved in water (5 mL) and ethanol (5 mL) is added over 5 minutes and the reaction was heated at 45° C. for 12 hours. The brown reaction is concentrated in vacuo to a dark brown oil and diluted with ethyl acetate (250 mL). The organic layer is washed with water (80 mL×2), saturated Na2S2O3 (80 mL), and brine (80 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (20-30% ethyl acetate/petroleum ether) gave the title compound as a white solid (7.24 g, 99.5%). Mp: 137-139° C. MS (ES−): 302 (M−H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[N:13]=[CH:14][C:15]3[N:16]([C:18](Br)=[CH:19][CH:20]=3)[CH:17]=1)=[O:11])[CH2:2]2.C(N(CC)CC)C.[CH2:29]([OH:32])[C:30]#[CH:31].[C:33]([OH:42])(=[O:41])[C@H:34]([C@@H:36]([C:38]([OH:40])=[O:39])[OH:37])[OH:35]>O1CCOCC1.[I+].[Cu+].Cl[Pd-2](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>[C:38]([CH:36]([CH:34]([C:33]([OH:42])=[O:41])[OH:35])[OH:37])([OH:40])=[O:39].[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[N:13]=[CH:14][C:15]3[N:16]([C:18]([C:31]#[C:30][CH2:29][OH:32])=[CH:19][CH:20]=3)[CH:17]=1)=[O:11])[CH2:2]2
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cn2c(Br)ccc2cn1
Reactant: C#CCO
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu+]
Agent: [I+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(N[C@H]1CN2CCC1CC2)c1cn2c(C#CCO)ccc2cn1
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 80 °C
Reaction time: 20 h
Yield: 24 %

Procedure:
To an argon sparged solution of N-[(3R)— 1-azabicyclo[2.2.2]oct-3-yl]-6-bromopyrrolo[1,2-a]pyrazine-3-carboxamide (0.230 g, 0.92 mmol), triethylamine (3.2 mL, 23.0 mmol) in dioxane (5 mL) is added copper (I) iodine (0.054 g, 0.28 mmol), propargyl alcohol (0.22 mL, 3.68 mmol), and dichlorobis(triphenylphosphino)-palladium (II) (0.063 g, 0.09 mmol). The reaction vessel is purged with argon, and stirred at 80° C. for 20 h at which point it is filtered through a plug of celite, concentrated to dryness, and the residue dissolved in CHCl3 (150 mL) that is washed with a solution containing 1:1 NH4OH/brine (5×35 mL). The residue is purified using silica gel chromatography (5% MeOH/CH2Cl2 gradient up to 10% MeOH/CH2Cl2) to give a pale orange colored oil that is salted with d-tartaric acid, and crystallized from EtOH/Et2O to give a tan solid. Yield 24%. HRMS (FAB) calcd for C18H20N4O2+H 325.1664, found 325.1664.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:16])[CH:6]=1)=[O:4].CO.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]([NH:14][CH2:13][CH2:12][N:7]1[C:8](=[O:11])[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6]1)=[O:16]
Reactant: COC(=O)c1ccc(=O)n(CCNC(=O)c2ccccn2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(=O)n(CCNC(=O)c2ccccn2)c1
Temperature: 60 °C

Procedure:
To a 10 ml round bottomed flask fitted with a magnetic stirrer bar was added 1,6-dihydro-1-[2-(2-pyridinylcarbonylamino)ethyl]-6-oxo-3-pyridinecarboxylic acid methyl ester (0.177 g, 0.59 mmol), methanol (1.4 ml), water (1.4 ml), and 15% aqueous sodium carbonate (1.4 ml). The resulting suspension was heated in a 60° C. oil bath for 1 hour during which time the mixture was completely solvated. Upon cooling to room temperature, acetic acid was added dropwise, with stirring, to a final pH of 5.5. The precipitated product was recovered by filtration, washed with water, and dried at 50° C. under high vacuum, MP: 266°-268° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([NH:19][CH3:20])(=[O:18])=[O:17])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:21][O:22][C:23]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:24]=1[NH2:25].O>C(O)C.Cl>[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([NH:19][CH3:20])(=[O:18])=[O:17])=[N:4][C:5]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:23]=2[O:22][CH3:21])=[N:6][CH:7]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Reactant: COc1ccc(N)c(OC)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc(OC)cc2OC)ncc1Br
Temperature: 25 °C

Procedure:
To a solution of 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (300 mg, 0.79 mmol), 2,4-dimethoxyaniline (181.5 mg, 1.18 mmol) in ethanol (3 mL), 1 N hydrochloric acid (0.03 mL) is added and stirred under reflux condition for 5 hours. The reaction mixture is cooled to room temperature, poured into water and extracted twice with ethyl acetate. The organic layer is successively washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1 to 1:1) to afford the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6]Cl.[Cl:8][C:9]1[CH:10]=[C:11]([NH2:23])[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[ClH:1].[Cl:8][C:9]1[CH:10]=[C:11]([N:23]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1
Reactant: ClCCNCCCl
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Cl
Product: Clc1ccc(Oc2ccc(N3CCNCC3)cc2Cl)cc1
Reaction time: 24 h

Procedure:
A mixture of 9 parts of 2-chloro-N-(2-chloroethyl)ethanamine hydrochlorine, 12.7 parts of 3-chloro-4-(4-chlorophenoxy)-benzenamine and 28 parts n-butanol is stirred and refluxed for 24 hours. The mixture is cooled and 3.5 parts of potassium carbonate are added. Stirring is continued for another 24 hours at reflux. The reaction mixture is filtered hot and the product is crystallized after cooling the filtrate. 2,2'-Oxybispropane is added and the precipitated product is filtered off. It is crystallized from a mixture of 2-propanol and 2,2'-oxybispropane, yielding 10.5 parts of 1-[3-chloro-4-(4-chlorophenoxy)phenyl]piperazine hydrochloride; mp. 187.7° C.
Reaction SMILES: [N:1]1[N:2]=[C:3]([NH:9][C:10](=[O:34])[CH2:11][N:12]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23](=[O:32])[C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[CH2:19][CH2:18]3)[C:13]2=[O:33])[N:4]2[CH2:8][CH2:7][S:6][C:5]=12.ClCCl.C(O)C.C(NCC)C>C(=O)=O>[N:1]1[N:2]=[C:3]([NH:9][C:10](=[O:34])[CH2:11][N:12]2[CH2:16][CH2:15][C@H:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23](=[O:32])[C:24]4[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=4)[CH2:19][CH2:18]3)[C:13]2=[O:33])[N:4]2[CH2:8][CH2:7][S:6][C:5]=12.[N:1]1[N:2]=[C:3]([NH:9][C:10](=[O:34])[CH2:11][N:12]2[CH2:16][CH2:15][C@@H:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23](=[O:32])[C:24]4[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=4)[CH2:19][CH2:18]3)[C:13]2=[O:33])[N:4]2[CH2:8][CH2:7][S:6][C:5]=12
Reactant: COc1ccc(C(=O)C2CCN(C3CCN(CC(=O)Nc4nnc5n4CCS5)C3=O)CC2)cc1
Agent: O=C=O
Solvent: CCO
Solvent: ClCCl
Solvent: CCNCC
Product: COc1ccc(C(=O)C2CCN([C@@H]3CCN(CC(=O)Nc4nnc5n4CCS5)C3=O)CC2)cc1
Product: COc1ccc(C(=O)C2CCN([C@H]3CCN(CC(=O)Nc4nnc5n4CCS5)C3=O)CC2)cc1

Procedure:
N-(5,6-Dihydrothiazolo[2,3-c][1,2,4]triazol-3-yl)-2-(3-(4-(4-methoxybenzoyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)acetamide (166 mg, 0.343 mmol) was eluted through a SCF column (70 mL/min flow rate) with 60% CO2 and 40% modifier (composed of 70% dichloromethane/ethanol and 0.2% diethylamine) to yield two enantiomerically enriched peaks N-(5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3-yl)-2-((S)-3-(4-(4-methoxybenzoyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)acetamide and N-(5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3-yl)-2-((R)-3-(4-(4-methoxybenzoyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)acetamide.
Reaction SMILES: Br[C:2]1[CH:3]([CH2:7][CH2:8][OH:9])[CH2:4][CH2:5][CH:6]=1.C([O-])([O-])=O.[Na+].[Na+].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>C1C=CC=CC=1.CCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:3]([CH2:7][CH2:8][OH:9])[CH2:4][CH2:5][CH:6]=1
Reactant: OCCC1CCC=C1Br
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Solvent: O
Product: OCCC1CCC=C1c1ccccc1F
Temperature: 80 °C

Procedure:
2-(2-Bromo-cyclopent-2-enyl)-ethanol Intermediate FIVE1 (1.21 g, 6.33 mmol) in benzene (40 mL), and Na2CO3 (7 mL, 2M) was treated with a solution of 2-fluorophenylboronic acid (1.08 g, 7.72 mmol) in EtOH (28 mL). Tetrakis(triphenylphosphine)palladium(0), Pd(PPh3)4 (0.38 g, 5 mol %) was added and the mixture was heated to 80° C. for 1.5 h. The mixture was diluted with water and extracted with diethyl ether (2×). The combined organic layers were dried over MgSO4, filtered and evaporated to dryness. The oil was purified by column chromatography on silica gel with 30% EtOAc:hexane to give 2-[2-(2-fluoro-phenyl)cyclopent-2-enyl]-ethanol Intermediate FIVE2 (1.21 g).