Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].C(=O)=O.C([Li])CCC.[F:28][C:29]([F:39])([F:38])[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br>O1CCCC1>[F:19][C:2]([F:18])([F:1])[C:3]1[CH:4]=[C:5]([CH:6]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[C:30]([C:29]([F:28])([F:38])[F:39])[CH:31]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCC
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(Cc1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
A solution of O,O-diethyl 3-trifluoromethylbenzylphosphonate (20.0 g, 67.5 mmol) in tetrahydrofuran (90 mL) was cooled to -70° C. (dry ice bath), under N2, and a solution of butyllithium (1.6M, in hexanes, 46.4 mL, 74.3 mmol) in 90 mL of dry tetrahydrofuran cooled to -70° C. (dry ice) was added. After 15 minutes, a solution of 3-trifluoromethylbenzylbromide (10.3 mL, 67.5 mmol)in tetrahydrofuran (90 mL) was added. The green reaction mixture turned yellow and was brought to room temperature and allowed to stir for 4 hours. The mixture was then quenched with H2O (200 mL), and extracted with ether (2×200 mL). The combined ether extracts were dried (MgSO4), filtered, and concentrated to dryness to give a yellow oil, 32.3 g. The crude product was chromatographed on a silica gel column. Elution with ethyl acetate/hexane (1:1) afforded analytically pure product as a pale yellow oil, 24.1 g (78.4 %). 300 MHz 1H NMR (CDCl3): δ, 3.16-4.20 (m,7H, PCH, PhCH2, 2(OCH2). MS: 455 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CCO>[NH2:8][C:6]1[N:5]2[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=[C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=1
Reactant: Nc1cc(Br)cc(N)n1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1cn2c(N)cc(Br)cc2n1

Procedure:
4-bromopyridine-2,6-diamine (3 g, 15.96 mmol) was dissolved in EtOH (300 mL). Ethyl bromopyruvate (2.34 mL, 16.8 mmol, 90% tech grade) was added. The mixture was heated at reflux for 5 h. The solvent was evaporated under reduced pressure to give a dark tan foam which was triturated with 200 mL of saturated NaHCO3 overnight. The solids were filtered, washed with 2×10 mL of saturated NaHCO3, then triturated with EtOAc (100 mL) twice, filtered and air dried to give the desired product as a tan powder weighing 3.15 g (70%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:36])[C:18]([N:20]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[C:26][C:27]3[S:31][CH:30]=[N:29][CH:28]=3)=[O:19])[CH:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[O:37][CH3:38].[OH-].[K+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:36])[C:18]([N:20]([C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[C:26][C:27]3[S:31][CH:30]=[N:29][CH:28]=3)=[O:19])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: CCOC(=O)C1c2cc(Br)c(OC)cc2CCN1C(=O)C(=O)N(CCCCC#Cc1cncs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCCCC#Cc1cncs1)C(C)(C)C)CC2
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 83.9 %

Procedure:
A solution of 300 mg of 17g in 3 ml of dioxane was mixed with 130 mg of KOH in 1 ml of water. The mixture was stirred at 50° C. for 1.5 hr, cooled, diluted with 20 ml of water, acidified to pH3 (0.2N HCl) and extracted with ethyl acetate. The extract was washed twice with water, dried and concentrated, to give 240 mg of acid 17h as a colorless foam.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]([C:16]([O:18][CH2:19][C:20](=[O:40])[C:21]2[CH:22]=[CH:23][C:24]3[C:33]4[CH:32]=[C:31]5[CH2:34][CH2:35][CH2:36][C:37](=[O:38])[C:30]5=[CH:29][C:28]=4[O:27][CH2:26][C:25]=3[CH:39]=2)=[O:17])[CH2:5]1.[Br-:41].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CO>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[C@H:6]([C:16]([O:18][CH2:19][C:20]([C:21]2[CH:22]=[CH:23][C:24]3[C:33]4[CH:32]=[C:31]5[CH2:34][CH2:35][CH:36]([Br:41])[C:37](=[O:38])[C:30]5=[CH:29][C:28]=4[O:27][CH2:26][C:25]=3[CH:39]=2)=[O:40])=[O:17])[CH2:5]1
Reactant: [Br-]
Reactant: COC[C@H]1CC(C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCCC4=O)N(C(=O)OC(C)(C)C)C1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: ClCCl
Product: COC[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
(4S)-1-tert-Butyl 2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl) 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (7.66 g, 13.9 mmol) was dissolved in a solution of DCM (100 mL) and MeOH (40 mL), then treated with pyridinium tribromide (4.90 g, 15.3 mmol). After stirring at RT for 1.75 h, the reaction mixture was diluted with DCM and washed successively with 10% HCl, saturated aqueous NaHCO3 and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure and the crude material was carried on without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:19][CH:20]1[CH2:22][O:21]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[CH:11][C:12]([O:16][CH2:19][CH:20]2[O:21][CH2:22]2)=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(O)cc(C)c1OCc1ccccc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1cc(OCC2CO2)cc(C)c1OCc1ccccc1

Procedure:
Using 4.22 g of the compound of Example 15, 2.7 ml of chloromethyloxirane, 2.42 g of anhydrous potassium carbonate and 100 ml of methyl ethyl ketone, reaction and workup carried out as in Example 1-A gave about 4.80 g of 1-(4-benzyloxy-3,5-dimethylphenoxy)-2,3-epoxypropane as yellow oil. Using the epoxy compound thus obtained, 4.04 g of 1-(2-methoxyphenyl)piperazine and 100 ml of dioxane, reaction and workup carried out as in Example 1-A followed by purification by column chromatography (silica gel, eluted with ethyl acetate:hexane=1:1) gave 5.96 g of white crystals, m.p. 93-94° C.
Reaction SMILES: Cl.C([O:9][C:10](=[O:28])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:27])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])C1C=CC=CC=1.C([O:32][CH2:33][CH3:34])(=O)C>CN(C)C=O.C(N(CC)CC)C>[NH:18]1[C:22](=[O:26])[CH2:23][CH2:25][C@H:34]1[C:33]([NH:24][C@H:23]([C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:10]([OH:9])=[O:28])=[O:27])=[O:26])[CH3:25])=[O:32]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 48 h

Procedure:
L-alanyl-L-prolyl-L-proline benzylester hydrochloride (2.46 g, 6 m mole) was dissolved in dimethylformamide (10 ml, and triethylamine (0.84 ml, 6m mole) was added thereto under cooling to neutralize it and then benzyloxycarbonyl-L-pyroglutamic acid N-hydroxysuccinimide ester (2.38 g, 6.6 m mole) was added thereto. The mixture was stirred for 2 days while the solution had been adjusted to a pH of about 7 with triethylamine and then ethyl acetate (150 ml) was added thereto. The solution was washed with 1N hydrochloric acid, 5% aqueous sodium bicarbonate and water in order. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. To the thus obtained residue, n-hexane was added to form a powder. This powder was purified by column chromatography. (Silica gel, developing solvent; chloroform:ethanol:ethyl acetate=5:1:5). The fractions of the main ingredient were collected together and then concentrated. To the residue, n-hexane was added to precipitate the powder. They were dissolved in methanol (50 ml) and then hydrogen gas passed through the solution in the presence of palladium-carbon as a catalyst for 4 hours. The catalyst was separated by filtration and the solvent was distilled off. The thus obtained residue was recrystallized with methanol-ether to give L-pyroglutamyl-L-alanyl-L-prolyl-L-proline (880 mg).
Reaction SMILES: [CH3:1][C:2]1(C)[O:6][C@H:5]2[O:7][C@H:8]([C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1.[C:18]([OH:21])(=[O:20])[CH3:19].C(OC(=O)C)(=O)C.OS(O)(=O)=O>C(Cl)Cl>[C:18]([O:21][C@@H:4]1[CH2:9][C@@H:8]([C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[CH2:11][CH3:12])[O:7][CH:5]1[O:6][C:2](=[O:3])[CH3:1])(=[O:20])[CH3:19]
Reactant: CC[C@H](OC(C)=O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC[C@H](OC(C)=O)[C@@H]1C[C@@H](OC(C)=O)C(OC(C)=O)O1
Temperature: 22 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
To a solution of [(1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propyl]acetate (compound 6f, 4.8 g, 20 mmol), acetic acid (12.2 g, 200 mmol) and acetic anhydride (10.2 g, 100 mmol) in anhydrous DCM (100 mL) was added concentrated H2SO4 (0.5 mL) at 0° C. After being stirred at 22° C. for 3 hours, the reaction was quenched by addition of saturated NaHCO3 solution. The organic layer was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column on silica gel (eluting with 1:8 EtOAc in petroleum ether) to afford 2.3 g of [(3R,5S)-2-acetoxy-5-[(1S)-1-acetoxypropyl]tetrahydrofuran-3-yl] acetate (compound 6g) as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>CCOC(C)=O>[CH3:21][O:20][N:19]([CH3:18])[C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
(R)-1-(tert-Butoxycarbonyl)piperidine-3-carboxylic acid (25 g, 0.11 mol, 1.0 equiv), N,O-dimethylhydroxylamine hydrochloride, (10.5 g, 0.14 mol, 1.25 equiv) and EDCI.HCl (26.3 g, 0.14 mol, 1.25 equiv) and diisopropylethylamine (48 mL, 0.28 mol, 2.5 equiv) were dissolved in solvent (400 mL) and stirred overnight at rt. The reaction mixture was diluted with EtOAc, washed with 5% aq HCl (2×150 mL), satd aq NaHCO3 (150 mL), brine (100 mL), and dried over Na2SO4. Concentration afforded (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (24.42 g, 82%) as a clear oil. The crude product was used for next step without further purification. MS ESI +ve m/z 295 (M+Na). 1H NMR (CDCl3) δ 4.19-4.00 (m, 2H), 3.77 (m, 3H), 3.12 (s, 3H), 2.79 (m, 2H), 2.64 (m, 1H), 1.89 (m, 1H), 1.71-1.52 (m, 2H), 1.51-1.33 (m, 10H).
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:11][CH2:12][C:13]1[C:22]2[C:17](=[C:18]([OH:24])[C:19]([OH:23])=[CH:20][CH:21]=2)[CH2:16][CH:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=1>>[ClH:9].[NH2:11][CH2:12][C:13]1[C:22]2[C:17](=[C:18]([O:24][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:19]([O:23][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:20][CH:21]=2)[CH2:16][CH:15]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:14]=1
Reactant: NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: NCC1=CC(c2ccccc2)Cc2c1ccc(OC(=O)c1ccccc1)c2OC(=O)c1ccccc1

Procedure:
Following the procedures described in Example 5, replacing trimethylacetyl chloride with benzoyl chloride and 1-aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydronaphthalene hydrochloride with the compound of Example 15, the title compound was prepared. m.p. 173°-182° C.; 1H NMR (CD3OD) δ: 2.88 (t, 1H), 3.05 (dd, 1H), 3.65-3.8 (m, 2H), 4.0-4.1 (br s, 1H+CH3OH), 6.35 (d, 1H), 7.05-7.35 (m, 10H), 7.35-7.55 (m, 3H), 7.9-8.0 (m, 4H), 8.5-8.65 (br s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[NH:23][C:22](=[O:30])[O:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:16][CH2:17][C:18]4([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[NH:23][C:22](=[O:30])[O:21]4)[CH2:19][CH2:20]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: O=C1Nc2ccccc2C2(CCNCC2)O1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)OC(=O)Nc3ccccc34)nn2)n1

Procedure:
The object product (72 mg, 76%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (51 mg), spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one hydrochloride (89 mg) and potassium carbonate (70 mg).
Reaction SMILES: [C:1]1([C:7](=[N:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.FC(F)(F)S(O[CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O>C1COCC1>[C:1]1([C:7](=[N:14][CH:15]([CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(OCCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CCC(F)(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.6 %

Procedure:
To a stirred solution of tert-butyl 2-((diphenylmethylene)amino)acetate (1 g, 3.39 mmol) in THF (20 mL) cooled to −78° C. under nitrogen atmosphere was added a 2M solution of LDA in THF (2.54 mL, 5.08 mmol) dropwise for 30 min. To this mixture was then added 3,3,3-trifluoropropyl trifluoromethanesulfonate (1.083 g, 4.40 mmol). The reaction was gradually warmed to rt and stirred for 4 h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride at 0° C. The reaction mixture was then extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with water (1×10 mL) and brine (1×10 mL), dried over sodium sulfate and then concentrated under reduced pressure. The crude oil was purified by silica gel column chromatography (2% ethyl acetate in hexane) to afford tert-butyl 2-((diphenylmethylene)amino)-5,5,5-trifluoropentanoate (800 mg, 2.02 mmol, 60% yield) as a yellow oil. LC/MS (ESI) m/e 391.9 [(M+H)+, calcd for C22H25F3NO2, 392.2]; LC/MS retention time (method E): tR=2.49 min.
Reaction SMILES: Cl[C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][OH:10])[N:7]=1.C(N(CC)CC)C.Cl.[CH3:29][O:30][CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:3]3[C:2]([N:35]4[CH2:36][CH2:37][CH:32]([CH2:31][O:30][CH3:29])[CH2:33][CH2:34]4)=[N:7][C:6]([CH2:8][CH2:9][OH:10])=[N:5][C:4]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: COCC1CCNCC1
Reactant: OCCc1nc(Cl)c2c(-c3ccc(F)cc3)csc2n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COCC1CCN(c2nc(CCO)nc3scc(-c4ccc(F)cc4)c23)CC1
Temperature: 55 °C
Yield: 89.7 %

Procedure:
2-[4-Chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2-yl]ethanol (150 mg, 0.0005 mol), triethylamine (0.214 mL, 0.00154 mol) and 4-(methoxymethyl)piperidine hydrochloride (0.091 g, 0.00055 mol) were dissolved in ethanol (5 mL) and warmed to 55° C. for 2 hrs. The reaction was then poured over ice and extracted with DCM. The organics were dried by passage through a PTFE frit and concentrated in vacuo to give 2-[5-(4-fluorophenyl)-4-[4-(methoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-2-yl]ethanol (180 mg). LCMS RT=4.33 min. M+1=402.
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[CH2:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=1.[N+:25]([CH:28]([CH3:30])[CH3:29])([O-:27])=[O:26]>CC#N>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH2:24][C:28]([CH3:30])([N+:25]([O-:27])=[O:26])[CH3:29])[C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: C=C(C(=O)OC)c1ccc(Cl)cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(CC(C)(C)[N+](=O)[O-])c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (33.68 mL, 225.2 mmol) was added to a solution of methyl 2-(4-chlorophenyl)acrylate (36.9 g, 187.7 mmol) and 2-nitropropane (20.23 mL, 225.2 mmol) in CH3CN (500 mL) at 0° C. under nitrogen. The mixture was warmed to room temperature and stirred overnight. The solution was concentrated in vacuo and subjected to column chromatography (20% EtOAc/hexanes) to give methyl 2-(4-chlorophenyl)-4-methyl-4-nitropentanoate (52.9 g, 98.66% yield) as a colourless oil. 1H NMR (CDCl3, 400 MHz) δ 7.31-7.29 (m, 2H), 7.21-7.19 (m, 2H), 3.66 (s, 3H), 3.60-3.57 (m, 1H), 2.87-2.81 (dd, 1H), 2.39-2.34 (dd, 1H), 1.56 (s, 3H), 1.55 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24]>O.C(O)C>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[S:7][CH2:6][C@@H:5]([C:8]([OH:10])=[O:9])[NH:4][C:1](=[O:3])[CH3:2])([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)N[C@@H](CSc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C

Procedure:
A mixture of 67.8 g of N-acetyl-L-cysteine and 100.8 g of sodium bicarbonate in 300 ml of water is added to 55.4 ml of o-fluoronitrobenzene in 1 l of ethanol. The reaction is heated to reflux for 3 hr with mechanical stirring and allowed to cool to room temperature. After removing the solids by filtration, the solution is concentrated to one fourth of the original volume and diluted with 1 l of water. The aqueous suspension is washed with 200 ml of ether and acidified to pH 1 with 12N aqueous hydrochloric acid. The resulting yellow precipitate is collected by filtration and dried in vacuo at 70° C. over phosphoruos pentoxide to afford S-(o-nitrophenyl)-N-acetyl-L-cysteine; m.p. 175°-176° C.; [α]D =+87.8° (c=1.15, absolute ethanol).
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24](I)=[C:23]3[O:28][CH2:29][O:30][C:22]=13)=[CH:17][C:16]([O:31][CH3:32])=[C:15]([O:33][CH3:34])[CH:14]=2)#[N:9].[CH2:35]([CH:38]1[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[NH:40][CH2:39]1)[C:36]#[CH:37]>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.C(OCC)(=O)C>[C:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:37]#[C:36][CH2:35][CH:38]3[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[NH:40][CH2:39]3)=[C:23]3[O:28][CH2:29][O:30][C:22]=13)=[CH:17][C:16]([O:31][CH3:32])=[C:15]([O:33][CH3:34])[CH:14]=2)#[N:9]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(I)c4c3OCO4)c2cc1OC
Reactant: C#CCC1CCS(=O)(=O)NC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(C#CCC4CCS(=O)(=O)NC4)c4c3OCO4)c2cc1OC
Temperature: -20 °C
Reaction time: 16 h
Yield: 22.8 %

Procedure:
N,N-Diisopropylamine (0.043 g) was added to a stirred mixture of 3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline (0.2 g), 4-(2-propynyl)-1,1-dioxotetrahydro-4H-thiazine (0.145 g), bis(triphenylphosphine)palladium(II) dichloride (0.071 g), cuprous iodide (0.024 g) and ethyl acetate (10 ml) that had been cooled to −20° C. The resultant mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with water and with a saturated brine solution, dried over magnesium sulphate and evaporated. The residue was triturated under a mixture of acetonitrile and water. The resultant solid was isolated and dried. There was thus obtained the title compound as a solid (0.05 g); NMR Spectrum: (DMSOd6) 2.97–3.04 (m, 4H), 3.12–3.18 (m, 4H), 3.72 (s, 2H), 3.83 (s, 3), 3.85 (s, 3H), 6.04 (s, 2H), 6.82 (d, 1H), 6.95 (d, 1H), 7.31 (s, 1H), 7.74 (s, 1H), 8.48 (s, 1H), 9.6 (s, 1H); Mass Spectrum: M+H+ 521.
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][C:9](=O)[CH:8]3[CH2:13][CH2:14][CH2:15][CH:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1COCC1>[F:1][C:2]1[C:11]2[NH:10][C:9](=[S:25])[CH:8]3[CH2:13][CH2:14][CH2:15][CH:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2c(F)cccc2C2CCCC12
Solvent: C1CCOC1
Product: Fc1cccc2c1NC(=S)C1CCCC21
Yield: 94.1 %

Procedure:
A solution of 6-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (100 mg, 0.48 mmol) and Lawesson's reagent (512 mg, 1.26 mmol) in THF (20 ml) is refluxed for 1.5 hours and concentrated by evaporation. Column chromatography of the residue with ethyl acetate-hexane yields 100 mg (93%) of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[N:8]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:31][CH:32]=2)[C:7]1=[O:18]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (45 g), 4′-(bromomethyl)biphenyl-2-carbonitrile (42.5 g), potassium carbonate (27 g) and acetonitrile (1 L) was stirred at 50° C. for 2 hr. The precipitated solid was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give the title compound as a colorless solid (64 g, 92%).