Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=3)[O:15][C:16]=2[CH3:17])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(Br)cc3)c(C)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(Br)cc1
Yield: 69.7 %

Procedure:
Reaction of benzoate 28 (320 mg, 0.71 mmol) and 2 M NaOH (10 mL) in dioxane (10 mL) gave acid 29 (216 mg, 70%) as a white solid: mp (DCM)>310° C.; 1H NMR δ 13.15 (br s, 1H, CO2H), 7.93 (br d, J=8.3 Hz, 2H, H-2, H-6), 7.84 (ddd, J=8.6, 2.3, 1.7 Hz, 2H, H-2′, H-6′), 7.68-7.73 (m, 4H, H-3, H-5, H-3′, H-5′), 4.70 (s, 2H, CH2SO2), 2.19 (s, 3H, CH3); MS m/z 437.0 (MH+, 100%), 439.0 (MH+, 100%). Anal. calcd for C18H14BrNO5S.½CH2Cl2: C, 47.08; H, 3.12; N, 2.89. Found: C, 47.09; H, 2.80; N, 2.99%.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:3][CH2:4][CH2:5]O.S([O-])([O-])(=O)=O.[Ca+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:43]Br>O.CCCCCC.CN(C)C=O>[Br:43][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CCCC(C)CCCC(C)CCCO
Reactant: BrBr
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCCC(C)CCCC(C)CCCBr

Procedure:
Into a 250 ml, three-necked, round-bottom flask equipped with a thermometer, serum cap, argon blubber and a magnetic stir bar was added 10 g (40 mmol) of 4,8,12-trimethyltridecanol, 30 ml of purified dimethylformamide (DMF) (stored over calcium sulfate prior to distillation) and 11.2 g (43 mmol) of triphenylphosphine. The solution was cooled to 0° C. before 2.19 ml (43 mmol) of bromine was added via syringe at such a rate that the temperature remained below 30° C. At the end of the addition a persistent orange color remained. The reaction was poured into 200 ml of hexane and 200 ml of water. The aqueous layer was extracted 3×200 ml of hexane. The combined organic layers were rinsed with 300 ml of saturated sodium bicarbonate, 100 ml brine, and were dried with 80 cc of sodium sulfate. The solvent was removed at reduced pressure with a rotary evaporator to afford a mixture of oil and solid. The mixture was triturated with hexane and filtered over a short plug of 40 g of silica gel eluting with hexane. Removal of the solvent left 10.7 g of colorless oil. Distillation through a 10 cm, vacuum jacqueted vigreaux afforded 9.7 g of colorless product, i.e. 1-bromo-4,8,12-trimethyltridecane, bp 119°-20° C. at 0.15 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH3:26])[N:25]=1)[C:5]([NH:7][CH:8]([NH:11][C:12]1[CH:22]=[CH:21][C:15]2[O:16][C:17]([F:20])([F:19])[O:18][C:14]=2[CH:13]=1)SC)=O.Cl.[CH2:28]([O:30][C:31](=[O:35])[CH2:32][NH:33][NH2:34])[CH3:29].C(N(C(C)C)C(C)C)C>CC(O)(C)C>[CH2:28]([O:30][C:31](=[O:35])[CH2:32][N:33]1[C:5]([C:4]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:2]([Cl:1])[CH:3]=2)=[N:7][C:8]([NH:11][C:12]2[CH:22]=[CH:21][C:15]3[O:16][C:17]([F:20])([F:19])[O:18][C:14]=3[CH:13]=2)=[N:34]1)[CH3:29]
Reactant: CCOC(=O)CNN
Reactant: CSC(NC(=O)c1cc(C)nc(Cl)c1)Nc1ccc2c(c1)OC(F)(F)O2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CCOC(=O)Cn1nc(Nc2ccc3c(c2)OC(F)(F)O3)nc1-c1cc(C)nc(Cl)c1
Temperature: 60 °C

Procedure:
Intermediate D2 (13.6 g; 0.0340 mol), 2-hydrazinylacetic acid ethyl ester, hydrochloride (1:1) (10.5 g; 0.0680 mol), N-ethyl-N-(1-methylethyl)-2-propanamine (13.2 g; 0.1020 mol) and t-BuOH (400 ml) were refluxed for 2 hours. The reaction mixture was then evaporated. Water was added and the product was extracted with CH2Cl2. The organic layer was dried on MgSO4, filtered and evaporated in vacuo. The residue was then heated to 60° C. in ethanol/HCl for 1 hour. The reaction mixture was partly evaporated and, the precipitate was filtered off and dried. Yield: 4.57 g of intermediate D3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)[CH:5]=[N:6][CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@H:10]3[CH2:14][CH2:13][CH2:12][NH:11]3)[CH:5]=[N:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2cncc(OC[C@H]3CCCN3)c2)cc1
Yield: 134 %

Procedure:
To a solution of 5-bromo-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine (300 mg, 0.84 mmol) and 4-chlorophenylboronic acid (263 mg, 1.68 mmol, Lancaster Chemical Co.) in toluene (10 mL) was added Pd(0) (25 mg) and Na2CO3 (1 mL of a 2M solution), and the mixture was heated at reflux for 6 hours. The solvent was removed under vacuum, and the residue was chromatographed on a silica gel column, eluting with 1:5 to 1:2 EtOAc/hexane to afford the title compound (325 mg, 100% yield). MS (CI/NH3) m/z 389 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 1.47 (s, 9h), 1.90 (m, 2H), 2.05 (br, 1H), 3.40 (br, 2H), 3.92 (br, 1H), 4.19 (br, 2H), 4.25 (br, 1H), 7.44 (m, 2H), 7.52 (m, 3H), 8.31 (m, 1H), 8.42 (s, 1H).
Reaction SMILES: C([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:28])[C:15]([C:23]([O:25]CC)=[O:24])=[CH:16][N:17]3[CH2:20][CH2:21][F:22])=[CH:12][C:11]=2[F:29])[CH2:6]1)(=O)C.C(O)C>Cl>[NH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:28])[C:15]([C:23]([OH:25])=[O:24])=[CH:16][N:17]3[CH2:20][CH2:21][F:22])=[CH:12][C:11]=2[F:29])[CH2:6]1
Reactant: CCOC(=O)c1cn(CCF)c2nc(N3CCC(NC(C)=O)C3)c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Product: NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CCF)C1
Yield: 74.8 %

Procedure:
A mixture of ethyl 7-ethylsulfonyl-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (19.8 g) obtained according to the Reference Example 2, 3-acetylaminopyrrolidine (10.2 g), triethylamine (7.4 ml), and ethanol (400 ml) was heated under reflux for 2 hours. After cooling, the resulting crystals were collected by filtration, and recrystallized from chloroform-ethanol to give 16.8 g of ethyl 7-(3-acetylamino-1-pyrrolidinyl)-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate melting at 269°-270° C. A solution of the above ester (15.0 g) in 20% hydrochloric acid (100 ml) was heated under reflux for 4 hours. After cooling, ethanol (100 ml) was added to the mixture and the resulting crystals were collected by filtration. The crystals were dissolved in hot water (100 ml) and treated with charcoal. The filtrate was adjusted to pH 8.5-9.0 by addition of aqueous 27% ammonia, and the resulting crystals were collected by filtration, washed with water, and dried to give 9.3 g of the compound 3, m.p. 251°-255° C.
Reaction SMILES: [K+].[Br-].N1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][NH:14]C(=S)[SH-]CC2C=CC=CC=2)=C1.F[C:26]1C=CC(CCNC(=S)[SH-]C)=C[CH:27]=1>>[NH2:14][CH2:13][C:12]1[CH:27]=[CH:26][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1
Reactant: C[SH-]C(=S)NCCc1ccc(F)cc1
Reactant: S=C(NCCc1c[nH]c2ccccc12)[SH-]Cc1ccccc1
Agent: [Br-]
Agent: [K+]
Product: NCc1ccc2ccccc2c1

Procedure:
Compound 27 (1.00 g, 5.8 mmol) in THF (20 mL) was added slowly to a solution of LAH (1.76 g, 46.4 mmol) in THF (45 mL) at 0° C. The solution was allowed to warm to room temperature and the reaction was stirred overnight. The reaction was cooled to 0° C. and quenched with H2O. The solids were filtered from the solution through celite and washed with hot THF. The filtrate was concentrated and the residue was dissolved in EtOAc (80 mL) and washed with 1 M HCl (3×30 mL). The aqueous layer was basified with 6 M NaOH to a pH of 12 and the precipitate was extracted with EtOAc (3×30 mL). The resulting organic solution was washed with brine (40 mL), dried with Na2SO4 and filtered. Concentration afforded a slightly yellow solid (510 mg, 56% yield). m.p. 55-56° C. 1H NMR (CDCl3) δ 7.80 (3H, ArH), 7.72 (s, 1H, ArH), 7.43 (m, 3H, ArH), 4.00 (s, 2H, ArCH2). 13C NMR (CDCl3) δ 140.6, 133.5, 132.5, 128.2, 127.7, 126.1, 125.8, 125.5, 125.1, 46.6. IR (KBr) vmax cm−1: 3362, 3291, 3050, 2915, 1950, 1596, 1507, 1358, 1273. GC: r.t.=8.97 min. EI-MS m/z (%) 157 (83, M+), 156 (100), 141 (15), 129 (49), 128 (40), 127 (24), 115 (10).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Cl)[CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1.BrC1C=[C:27]([O:31]C)C=CC=1>>[NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:31][CH3:27])[CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1
Reactant: COc1cccc(Br)c1
Reactant: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(CCN)cc2n(C)c1=O
Product: COc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CCN)c1

Procedure:
The title compound was prepared analogously to Intermediate B by replacing 1-bromo-3-chlorobenzene with 3-bromoanisole;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:12]N(C)C)=O)=[CH:5][CH:4]=1.Cl.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[NH:31])=[CH:28][CH:27]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]2[N:32]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:11]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[CH:12][N:31]=2)=[CH:28][CH:27]=1
Reactant: N=C(N)c1ccc(Cl)cc1
Reactant: COc1ccc(C(=O)C(=CN(C)C)c2ccc(OC)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cnc(-c3ccc(Cl)cc3)nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 9.34 g. of (4-methoxyphenyl)-[1-(4-methoxyphenyl)-2-dimethylaminovinyl]ketone, 5.73 g. of 4-chlorobenzamidine hydrochloride, and 6.73 g. of potassium t-butoxide in 200 ml. of toluene was allowed to reflux for 2.5 hours and then stirred overnight at room temperature. The suspension was extracted twice each with 200 ml. of water. The combined water extracts were back-extracted with 100 ml. of toluene. The combined toluene solutions were washed with 100 ml. of a saturated sodium chloride solution. The organic solution was then dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography over silica gel. The appropriate fractions were evaporated to dryness and crystallized from Skelly B to provide 3.97 g. of the desired title product, m.p. about 151°-153° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17](B(O)O)[CH:18]=1)[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[CH2:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=2)[CH:18]=1)[CH3:11]
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: N#Cc1cc(Cl)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOc1ccc(F)c(-c2ccnc(C#N)c2)c1
Yield: 85.5 %

Procedure:
A mixture of 4-chloropyridine-2-carbonitrile (4.1 g, 29.56 mmol) and (5-ethoxy-2-fluoro-phenyl)boronic acid (5982.6 mg, 32.52 mmol) in monoglyme (150 mL) was treated with sodium carbonate (29.56 mL, 59.13 mmol) and then PdCl2(PPh3)2 (1037.5 mg, 1.48 mmol) and the mixture was refluxed under argon. After 2 hrs the DME was evaporated and ethyl acetate (200 ml) and water were added and the product was extracted into ethyl acetate (3 times). The extracts were dried (Na2SO4) and concentrated. Chromatography on silica gel (0-50% ethyl acetate in isohexane, using a SNAP340 cartidge on a Biotage SP4) gave 4-(5-ethoxy-2-fluoro-phenyl)pyridine-2-carbonitrile (D111) (6.12 g) as an off white solid;
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[O:14][C:13](=[O:15])[NH:12][CH2:11]2)[C:5]([O:16][CH2:17][CH3:18])=[C:4]([CH:19](O)[CH3:20])[CH:3]=1.CN(C)C=O.S(Cl)([Cl:29])=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[O:14][C:13](=[O:15])[NH:12][CH2:11]2)[C:5]([O:16][CH2:17][CH3:18])=[C:4]([CH:19]([Cl:29])[CH3:20])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOc1c(C(C)O)cc(Cl)c(C#N)c1C1CNC(=O)O1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1c(C(C)Cl)cc(Cl)c(C#N)c1C1CNC(=O)O1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-(2-oxo-1,3-oxazolidin-5-yl)benzonitrile (58 mg, 0.19 mmol) (mixture of four diastereomers from step 4), N,N-dimethylformamide (36 μL) in methylene chloride (1 mL), thionyl chloride (40.0 μL, 0.56 mmol) was added and the mixture was stirred at room temperature for 20 minutes The mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated to give the desired compound as a mixture of four diastereomers, 55 mg, 91%. LCMS calculated for C14H15Cl2N2O3 (M+H)+: m/z=329.0; found: 329.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-])=O>C(O)C.[Pd]>[N:20]1([CH2:19][CH2:18][CH2:17][O:16][C:7]2[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(OCCCN2CCOCC2)c(-c2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OCCCN2CCOCC2)c(-c2ccccc2)c1
Reaction time: 8 h
Yield: 46.6 %

Procedure:
4-[3-(5-Nitro-biphenyl-2-yloxy)-propyl]-morpholine (u, 400 mg, 1.1 mmol) was dissolved in 10 mL ethanol and hydrogenated at 1 atm. using 10% Pd—C as a catalyst. After the reaction was allowed to stir overnight, the reaction mixture was filtered and the solvent was evaporated. The residue was purified by silica gel chromatography (eluent: 5% methanol/DCM) to afford 160 mg 6-(3-morpholin-4-yl-propoxy)-biphenyl-3-ylamine (v): m/e: 312.18, MS (ES+): 313.2.
Reaction SMILES: Cl[S:2]([CH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)(=O)=O.[CH2:12]([O:19]C(C1(CS(N2CCN(C3C=CC(F)=CC=3)CC2)(=O)=O)CCOCC1)=O)[C:13]1C=CC=CC=1.FC1C=CC(N2CCN(S(CC3(C(O)=O)CCOCC3)(=O)=O)CC2)=CC=1>>[C:12]([S:2][CH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)(=[O:19])[CH3:13]
Reactant: O=S(=O)(Cl)CC1CCOCC1
Reactant: O=C(OCc1ccccc1)C1(CS(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)CCOCC1
Agent: O=C(O)C1(CS(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)CCOCC1
Product: CC(=O)SCC1CCOCC1

Procedure:
MS (ESI): 331 (MNa+); 4-(chlorosulfonylmethyl)tetrahydropyran-4-(carboxylic acid benzyl ester): MS (ESI): 354 (MNa+); 4-[4-(4-fluorophenyl)piperazine-1-sulfonylmethyl]tetrahydropyran-4-carboxylic acid benzyl ester: MS (ESI): 477 (MH+), 499 (MNa+); 4-[4-(4-fluorophenyl)piperazine-1-sulfonylmethyl]tetrahydropyran-4-carboxylic acid: MS (ESI): 387 (MH+), 409 (MNa+).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][CH2:12][C:13]([O:15]CC)=[O:14])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:3][CH2:2]1
Reactant: CCOC(=O)COC1CCOc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COC1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-(chroman-4-yloxy)acetate (403 mg, 1.71 mmol) and sodium hydroxide aqueous solution (2 M, 1.71 mL, 3.41 mmol) in methanol (10 mL) was stirred at rt for 3 h. Then, hydrochloric acid (2 M, 1.71 mL, 3.41 mmol) was added, and the solvent was removed in vacuo. The residue was suspended in THF, and the mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give 370 mg (quant) of the title compound as a colorless oil. This was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5](=[CH2:9])[C:6]([O-])=[O:7].C(N=C=N)C.[CH2:16]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:17]=[CH2:18]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]([C:6](=[O:7])[N:19]([CH2:16][CH:17]=[CH2:18])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH2:9]
Reactant: C=CCNCc1ccccc1
Reactant: C=C(CC(=O)OC)C(=O)[O-]
Agent: CCN=C=N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCN(Cc1ccccc1)C(=O)C(=C)CC(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 48.8 %

Procedure:
587 mg of 2-methylene-succinate 4-methyl ester (4.07 mM), 781 mg of 143-(dimethylamino)propyl]-3-ethylcarbodiimide (4.07 mM) and 75 mg of 4-(dimethylamino)pyridine (0.61 mM) were added to the reaction solution containing 300 mg of allylbenzylamine (2.04 mM) dissolved in methylene chloride solution (0.5M) with stirring for 10 hrs at room temperature. After the resulting mixture was washed with 5% HCl solution (10 ml), the mixture was diluted with ethyl acetate, washed with 10 ml of solution mixture mixed with saturated NaHCO3 solution and saturated NaCl solution to separate into an organic layer and water layer. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with EtOAc and hexanes (1:1) as an eluant to give 272 mg of 3-(allyl-benzyl-carbamoyl)-but-3-enoic acid methyl ester (o) (yield: 49%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:17]([C@:11]1([C:14]([N:29]2[CH2:28][CH:27]=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:31][CH2:30]2)=[O:16])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)([CH3:19])[CH3:18]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CC=C(c3ccccc3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
In a dried flask, (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (200 mg, 0.7 mmol) and 4-phenyl-1,2,3,5-tetrahydropyridine (160 mg, 0.81 mmol) were suspended in methylene chloride (4 mL) under N2. Triethylamine (0.22 g, 2.2 mmol) was added followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.36 g, 0.81 mmol). The reaction was stirred overnight at room temperature and quenched by addition of saturated NaHCO3 solution. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered and concentrated. Purification by flash chromatography on silica gel (gradient: 0-45% B over 15 min. Bottle A=hexanes, bottle B=EtOAc) to give 234 mg (80%) of desired product. MS calculated for C25H36N2O3: (M+H) 413; found 413.2.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[N:15]=[C:14](Cl)[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:12]=2[C:11](=[O:26])[N:10]([CH3:27])[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([N:8]1[C:16]2[N:15]=[C:14]([O:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([C:30]([F:38])([F:39])[F:29])[CH:32]=3)[N:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[C:12]=2[C:11](=[O:26])[N:10]([CH3:27])[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccc(Cl)cc2)n(Cc2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)c2c(nc(Oc3cccc(C(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(Cc2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 39.5 %

Procedure:
To a solution of 3-benzyl-8-chloro-7-(4-chlorobenzyl)-1-methyl-1H-purine-2,6(3H,7H)-dione (60 mg, 0.145 mmol) in DMF (3 mL) was added 3-(trifluoromethyl)phenol (35 mg, 0.215 mmol) followed by potassium carbonate (40 mg, 0.29 mmol). The mixture was stirred at 100° C. for 2 h. The mixture was diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The give crude product was purified by preparative HPLC to give 3-benzyl-7-(4-chlorobenzyl)-1-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione (31 mg, 41.7% yield) as white solid. 1H-NMR (CDCl3) δ 7.65(s, 1H), 7.58-7.57(m, 2H), 7.45-7.41(m, 5H), 7.33-7.27(m, 5H), 5.42(s, 2H), 5.09(s, 2H), 3.41(s, 3H). LCMS retention time 3.649 min; LCMS (M+H) 541.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][CH2:6]Cl.[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][CH2:6][S:14][C:13](=[NH:12])[NH2:15]
Reactant: ClCCc1ccc(Cl)c(Cl)c1
Reactant: NC(N)=S
Solvent: CCO
Product: N=C(N)SCCc1ccc(Cl)c(Cl)c1

Procedure:
3,4-Dichlorophenethyl chloride (0.8 g., 0.004 mol.) and thiourea (0.26 g., 0.0035 mol.) in 25 ml. of ethanol were refluxed for two days. The mixture was concentrated and the residue treated with ether to give a solid which was recrystallized from acetone to yield carbamimidothioic acid 3,4-dichlorophenethyl ester, m.p. 135°-139° C.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.C(N(CC)CC)C.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=[O:19]>ClCCl>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=[O:19])[CH2:3][CH2:2]2
Reactant: O=C(Cl)Oc1ccc(Br)cc1
Reactant: C1CN2CCC(CC2)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc(Br)cc1)N1CCN2CCC1CC2
Temperature: 0 °C

Procedure:
0.379 g (3.0 mmol) of 1,4-diazabicyclo[3.2.2]nonane and 0.84 ml (6.0 mmol) of triethylamine in 5 ml of dichloromethane are introduced into a 50-ml three-necked flask, the mixture is cooled to 0° C., 0.730 mg (3.1 mmol) of 4-bromophenyl chloroformate in solution in 3 ml of dichloromethane is added dropwise and the stirring is maintained at 0° C. for 10 min.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=2)=[O:12])[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-].[Na+].Cl>CO>[CH3:7][C:4]1[N:3]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][CH:19]=2)=[O:12])[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(NC(=O)NCCn2c(C)ccc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C)n1CCNC(=O)Nc1ccc(C(=O)O)cc1

Procedure:
3.3 g (0.01 mol) of N-(2-(2,5-dimethyl-1-pyrrolyl)ethyl)-N'-(4-ethoxycarbonylphenyl)urea, prepared as in Example 7, are stirred with 12 ml of methanol and 10 ml of 1 N sodium hydroxide solution at room temperature for 1 h and then acidified with dilute hydrochloric acid. The precipitated product is filtered off with suction and dried. Yield: 1.5 g (50% of theory), Melting point: 248°-250° C. Elemental analysis: C16H19N3O3 (301.35) calculated: C 63.8 H 6.4 N 13.9 O 15.9 found: C 63.4 H 6.2 N 13.9 O 16.3