Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[SH-].[Na+].[CH3:4][C:5]1([CH3:14])[O:9][N:8]=[C:7]([S:10]([CH3:13])(=O)=O)[CH2:6]1.BrC[C:17]1[C:18]([C:29]([F:32])([F:31])[F:30])=[N:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]=1[F:22].O>CN(C)C=O>[CH3:4][C:5]1([CH3:14])[O:9][N:8]=[C:7]([S:10][CH2:13][C:17]2[C:18]([C:29]([F:32])([F:31])[F:30])=[N:19][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:21]=2[F:22])[CH2:6]1
Reactant: Fc1c(CBr)c(C(F)(F)F)nn1-c1ccccc1
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Agent: [Na+]
Agent: [SH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(SCc2c(C(F)(F)F)nn(-c3ccccc3)c2F)=NO1
Reaction time: 2 h
Yield: 37.4 %

Procedure:
9.3 g of sodium hydrosulfide hydrate (purity: 70%, 116.3 mmoles) was added to a solution of 18.7 g (105.7 mmoles) of 5,5-dimethyl-3-methylsulfonyl-2-isoxazoline (present compound No. 2-1) dissolved in 300 ml of N,N-dimethylformamide. The mixture was stirred for 2 hours. The reaction system was ice-cooled. Thereto was added a solution of 30.3 g (93.8 mmoles) of 4-bromomethyl-5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole dissolved in 200 ml of N,N-dimethylformamide. The mixture was stirred at 0° C. for 30 minutes to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 13.11 g (yield: 37.4%) of 5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline as a yellow oily substance.
Reaction SMILES: C[C:2]1[C:6]([CH2:7][C:8]2[S:23][C:11]3[N:12]([CH2:19][CH:20](C)C)[C:13](=[O:18])[N:14]([CH3:17])[C:15](=[O:16])[C:10]=3[C:9]=2[C:24]([N:26]2[CH2:30][C@:29]([CH3:32])([OH:31])[CH2:28][O:27]2)=[O:25])=[C:5](C)NN=1.ON1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36]1.[CH2:44](N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[OH:31][C@:29]1([CH3:32])[CH2:28][O:27][N:26]([C:24]([C:9]2[C:10]3[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[N:12]([CH:19]([CH3:44])[CH3:20])[C:11]=3[S:23][C:8]=2[CH2:7][C:6]2[CH:5]=[N:36][N:37]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:2]=2)=[O:25])[CH2:30]1
Reactant: On1nnc2ccccc21
Reactant: Cc1n[nH]c(C)c1Cc1sc2c(c1C(=O)N1C[C@](C)(O)CO1)c(=O)n(C)c(=O)n2CC(C)C
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)n1c(=O)n(C)c(=O)c2c(C(=O)N3C[C@](C)(O)CO3)c(Cc3cnn(-c4ccccc4)c3)sc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the product of part c) (0.5 g), the product of example 1 part d) (0.18 g), and 1-hydroxybenzotriazole (0.36 g) in dichloromethane (10 ml) was added triethylamine (0.36 ml) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.45 g) and the mixture stirred at ambient temperature under nitrogen for 18 hr. It was diluted with water and extracted with dichloromethane, the organic extracts were washed successively with 1.0N sodium hydroxide and water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with ethyl acetate/methanol (99:1) followed by ethyl acetate/methanol (49:1) to give the title compound as a solid (0.14 g).
Reaction SMILES: O.[C:2](Cl)(=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:9][NH:10][C:11](=[O:29])[CH2:12][NH:13][C:14](=[O:28])[C:15]1[C:20]([I:21])=[C:19]([NH2:22])[C:18]([I:23])=[C:17]([C:24]([OH:26])=[O:25])[C:16]=1[I:27].CNC(=O)[C@H](CC1C=CC=CC=1)NC(=O)C1C(I)=C(N)C(I)=C(C(O)=O)C=1I>CC(N(C)C)=O>[CH3:9][NH:10][C:11](=[O:29])[CH2:12][NH:13][C:14](=[O:28])[C:15]1[C:20]([I:21])=[C:19]([NH:22][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6])[C:18]([I:23])=[C:17]([C:24]([OH:26])=[O:25])[C:16]=1[I:27]
Reactant: CNC(=O)CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: CCCCC(=O)Cl
Agent: CNC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCC(=O)NC)c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under agitation and water cooling, 31.5 ml. of valeroyl chloride is added dropwise to 45.8 g. (0.073 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine methylamide (IV a), m.p. 252°-253° C. (under decomposition), in 120 ml. of dimethylacetamide. After agitating the reaction mixture overnight at room temperature, the product is precipitated by adding water; then, the product is vacuum-filtered and purified by dissolving the corresponding sodium salt and separation of the free acid by the addition of a mineral acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:21]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[F:30][CH:31]([F:41])[C:32]1[N:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=1>>[NH2:21][C:10]1[S:11][CH2:12][C@@H:13]2[C@@H:14]([C:17]([F:20])([F:18])[F:19])[O:15][CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:38]([C:35]3[CH:34]=[N:33][C:32]([CH:31]([F:41])[F:30])=[CH:37][N:36]=3)=[O:39])[CH:3]=[CH:4][C:5]=2[F:29])[N:9]=1
Reactant: O=C(O)c1cnc(C(F)F)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(C(F)F)cn4)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1

Procedure:
Synthesized from tert-butyl [(4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-difluoromethyl-pyrazine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3) δ ppm 2.80 (dd, J=13.8, 3.7 Hz, 1H), 3.11 (dd, J=13.6, 2.8 Hz, 1H), 3.31-3.41 (m, 1H), 3.86 (d, J=8.3 Hz, 1H), 4.57 (d, J=8.3 Hz, 1H), 4.64 (dt, J=14.7, 7.1 Hz, 1H), 4.75 (br s, 2H), 6.69 (t, J=56.3 Hz, 1H), 7.07 (dd, J=11.6, 8.8 Hz, 1H), 7.57 (dd, J=7.1, 2.8 Hz, 1H), 7.87 (dt, J=8.5, 3.6 Hz, 1H), 8.85 (s, 1H), 9.45 (s, 1H), 9.58 (br. s., 1H)
Reaction SMILES: [OH:1][CH:2]1[O:10][C@H:9]([C:11](=[O:13])[OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[NH2:14][C@H:15]([C:20]([NH:22][C@H:23]([C:31]([O:33]CC1C=CC=CC=1)=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17]>CN(C=O)C.O.[Pd]>[OH:1][CH:2]1[O:10][C@H:9]([C:11](=[O:12])[OH:13])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[NH2:14][C@H:15]([C:20]([NH:22][C@H:23]([C:31]([OH:33])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17]
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C(O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 5 h
Yield: 98 %

Procedure:
GlcA-Ile-Phe-OBzl (1.04 g, 1.9 mmol) was hydrogenolyzed in presence of palladium/activated charcoal (10% Pd) (200 mg) in DMF-water (9:1, v/v) solution for 5 h. After removal of the catalyst by filtration the solution was evaporated to dryness and the product was recovered by lyophilization from water with 98% yield (0.85 g); mp 173°-174° C.; [α]54625 =+3,36 (c=1, MeOH); Rf(A) =0.15.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[C:5]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[N:4]=1>O1CCOCC1.CO>[CH3:32][N:29]1[CH2:28][CH2:27][N:26]([C:5]2[CH:6]=[C:7]([C:9]3[CH:18]=[C:17]4[C:12]([CH2:13][CH2:14][NH:15][CH2:16]4)=[CH:11][CH:10]=3)[N:8]=[C:3]([NH2:2])[N:4]=2)[CH2:31][CH2:30]1.[ClH:1]
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CC4)nc(N)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6 mL of 4N HCl in dioxane was added to a solution of tert-butyl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.90 g, 2.1 mmol) in methanol (5 mL). The mixture was stirred at r.t. for 2 h. The mixture was concentrated under reduced pressure. The residue was washed with ether and dried under vacuum to afford the desired product as an HCl salt (0.83 g). Analytic LCMS (M+H)+: m/z=325.4.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Br[CH:7]([C:15]([CH3:17])=[O:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].O>CN(C=O)C>[C:1]([O:4][CH:7]([C:15]([CH3:17])=[O:16])[C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)C(Br)C(=O)OC(C)(C)C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC(C(C)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of sodium acetate (30.76 g, 375 mmol) in DMF (250 mL) was added dropwise tert-Butyl 2-bromo-acetoacetate (59.27 g, 250 mmol). After stirring at ambient temperature for 90 minutes, water (415 mL) was added, followed by extraction with ethyl acetate (3×325 mL). The combined organic layers were washed with water (3×325 mL) and brine (325 mL), dried over Na2SO4 and after filtration, the solvent was removed in vacuo. The resulting oil was purified by distillation (12 mbar, 128°)
Reaction SMILES: N1CC[O:4]CC1.[CH2:7]1[N:14]([CH2:15][CH2:16][NH+:17]([CH2:28][C:29]([O-:31])=[O:30])[CH2:18][CH2:19][N:20]2[CH2:27][C:25](=[O:26])[O:24][C:22](=[O:23])[CH2:21]2)[CH2:13][C:11](=[O:12])[O:10][C:8]1=[O:9].[OH2:32]>>[CH2:16]([N:17]([CH2:28][C:29]([OH:31])=[O:30])[CH2:18][CH2:19][N:20]([CH2:27][C:25]([OH:26])=[O:4])[CH2:21][C:22]([OH:24])=[O:23])[CH2:15][N:14]([CH2:7][C:8]([OH:10])=[O:9])[CH2:13][C:11]([OH:12])=[O:32]
Reactant: C1COCCN1
Reactant: O
Reactant: O=C([O-])C[NH+](CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1
Product: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Reaction time: 24 h

Procedure:
To a 2-liter round bottom flask containing morpholine (400 mL, 4.60 mol) was added DTPA dianhydride (71.5 g, 200 mmol) followed by 150 mL of water. The reaction was stirred for 24 hours and concentrated. The crude material was evaporated three times from 400 mL water and then stirred with 1 L of dry ethanol at 50° C. for 18 hours. The suspension was filtered and the solids were purified by ion-exchange chromatography on AGl-X8 (hydroxide form) resin eluting with water followed by 0.2 N acetic acid to afford 53.0 g of DTPA-BMO.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)[S:8][CH:9]=1)=[N+]=[N-].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:34].C(N(CC)CC)C>CO.[OH-].[OH-].[Pd+2]>[Si:15]([O:14][CH:12]1[CH2:13][N:10]([C:7]2[S:8][CH:9]=[C:5]([CH2:4][NH:1][C:33]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:34])[N:6]=2)[CH2:11]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)[Si](OC1CN(c2nc(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
1-(4-Azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (1.06 g, 2.37 mmol) (obtained as described in Reference Example 62(1)) in methanol (53 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide on charcoal (1.05 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was dissolved in methylene chloride (53.2 ml). To the mixture were added p-nitrobenzyl chloroformate (0.76 g, 3.52 mmol) and triethylamine (0.5 ml, 3.59 mmol) in an ice bath, and the mixture was stirred at room temperature overnight. After checking the completion of the reaction, the mixture was distilled under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:ethyl acetate (3:2) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (867.2 mg, yield 61%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:20])=[C:15]([O:18]C)[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[BrH:23]>C(O)(=O)C>[BrH:23].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:20])=[C:15]([OH:18])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:21][CH:22]=1
Reactant: COc1cc2c(cc1O)CCNC2COc1ccc(Cl)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1cc2c(cc1O)C(COc1ccc(Cl)cc1)NCC2
Temperature: 100 °C

Procedure:
A mixture of 1-(4-chlorophenoxy)methyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (100 mg), 47% hydrobromic acid (3 ml) and acetic acid (1.5 ml) was heated at 100°C in an oil bath for 4.5 hours, and to the mixture was further added 47% hydrobromic acid (0.5 ml), and the mixture was continuously heated for 0.5 hour. After the reaction, the solvent was distilled off under reduced pressure. The amorphous residue was dissolved in acetone, and to the solution was added ether, and the mixture was allowed to stand. The precipitated cyrstals were collected by filtration to give 1-(4-chlorophenoxy)methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (97 mg), mp 232° to 233°C. The product was identified with a sample by I.R. spectrum and N.M.R. spectrum.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[C:18](O)([CH3:21])([CH3:20])[CH3:19].[N+](C)([O-])=O.[F:27][B-:28]([F:31])([F:30])[F:29].[H+]>C(OCC)C>[F:27][B-:28]([F:31])([F:30])[F:29].[C:18]([N+:9]1[O:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]2[CH:16]=[C:2]([Cl:1])[C:3]([CH3:17])=[CH:4][C:5]=12)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)O
Reactant: Cc1cc2noc(-c3ccccc3)c2cc1Cl
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: Cc1cc2c(cc1Cl)c(-c1ccccc1)o[n+]2C(C)(C)C
Temperature: 25 °C
Reaction time: 85 h

Procedure:
To a suspension of 59 g. of 5-chloro-6-methyl-3-phenyl-2,1-benzisoxazole, 26.6 ml. of tert.-butanol and 740 ml. of nitromethane, is added dropwise 45.7 g. of a 50% aqueous solution of tetrafluoroboric acid. The resulting suspension is stirred at room temperature for 85 hours. The reaction mixture is diluted with approximately 10 liters of diethyl ether and the crystalline precipitate formed is isolated by filtration to yield 1-tert.-butyl-5-chloro-6-methyl-3-phenyl-2,1-benzisoxazolium tetrafluoroborate, m.p. 164°-166°C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[O:20]1[CH2:23][CH:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:21]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:27]3[CH2:28][CH2:29][CH:24]([CH:22]4[CH2:23][O:20][CH2:21]4)[CH2:25][CH2:26]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Reactant: C1CC(C2COC2)CCN1
Product: Clc1nc(N2CCOCC2)c2nc(CN3CCC(C4COC4)CC3)ccc2n1

Procedure:
4-(6-(Bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.199 g) was reacted with 4-(oxetan-3-yl)piperidine via General Procedure B to afford 0.11 g 4-(2-chloro-6-((4-(oxetan-3-yl)piperidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:29])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1.O>C1C=CC=CC=1>[CH3:27][O:26][C:24]([CH:23]([OH:28])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:29])=[CH:17][CH:18]=1)=[O:25]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)C(O)Cc1ccc(OCC(C)=O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C(O)Cc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1
Yield: 68.9 %

Procedure:
A mixture of 1.16 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 1.71 g of methyl 3-[4-(2-oxopropoxy)phenyl]lactate (prepared as described in Preparation 6) and 40 ml of benzene was heated under reflux for 3.5 hours, whilst the water being formed during the reaction was continuously removed. After completion of the reaction, the benzene used in the reaction was removed by distillation under reduced pressure, and the residue was dissolved in 50 ml of absolute methanol. 2.04 g of sodium cyanoborohydride were added, whilst ice-cooling, to the solution, and the resulting mixture was allowed to react overnight at room temperature. At the end of this time, methanol was removed by distillation under reduced pressure, and the resulting residue was mixed with ethyl acetate and with an aqueous solution of sodium chloride. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 1.9 g of the title compound having an Rf=0.30 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CS(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Clc1ccccn1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccccn3)CC2)cc1

Procedure:
From 1-(4-nitro-phenyl)-piperazine and 2-chloropyridine, by heating in DMSO to give 1-(4-nitro-phenyl)-4-pyridin-2-yl-piperazine then catalytic hydrogenation over Raney nickel in methanol.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C.O>C(#N)C.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>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:14]#[C:13][CH2:12][OH:15])=[CH:3][CH:4]=1
Reactant: C#CCO
Reactant: COC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(C#CCO)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.5 %

Procedure:
To a solution of methyl 4-iodobenzoate (20 g, 76 mmol), propargyl alcohol (5.55 g, 99.0 mmol) and triethylamine (20 mL) in acetonitrile (200 mL) was added dichlorobis(triphenylphosphine)palladium(II) (1.55 g, 2.21 mmol), followed by Cul (454 mg, 2.38 mmol). The reaction mixture was stirred at room temperature for 24 h. Water was added and the aqueous solution was washed with EtOAc (3×). The organic solutions were combined, dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (9:1 hexanes:EtOAc to 4:1 hexanes:EtOAc) provided 4-(3-hydroxy-prop-1-ynyl)-benzoic acid methyl ester (12.65 g).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1.[ClH:38]>C(#N)C.CC(C)=O.C(OCC)C>[ClH:29].[ClH:38].[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][N:20]2[CH2:21][CH2:22][N:17]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:16]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:8]=3)[CH2:18][CH2:19]2)=[CH:33][CH:32]=1
Reactant: c1ccc(-c2cc(N3CCNCC3)c3ccccc3c2)cc1
Reactant: Cc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Solvent: CC(C)=O
Product: Cc1ccc(CN2CCN(c3cc(-c4ccccc4)cc4ccccc34)CC2)cc1
Temperature: 5 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-phenyl-1-(1-piperazinyl)-naphthalene (17.9 g) in acetonitrile (280 cc), there is added potassium carbonate (8.6 g) and then, in the course of 20 minutes, a solution of α-chloro-p-xylene (8.7 g) in acetonitrile (50 cc), at a temperature in the region of 20° C., and stirring is continued for 16 hours. The insoluble material which is formed is separated by filtration. The solution obtained is evaporated under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is dissolved in methylene chloride (35 cc) and the solution poured onto silica (1 kg) contained in a column 7.5 cm in diameter. Elution is performed with a mixture (3 liters) of methylene chloride and methanol (99:1 by volume) and the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in acetone (250 cc). The solution is cooled to a temperature in the region of 5° C., a 2.5N solution (52 cc) of anhydrous hydrochloric acid in ethyl ether is added and stirring is maintained for approximately 4 hours. The precipitates formed is separated by filtration and washed with ethyl ether ether (3×25 cc). 1-[4-(4-Methylbenzyl)-1-piperazinyl]-3-phenylnaphthalene dihydrochloride (19 g), m.p. 252° C., is thereby obtained.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([P:10](=[S:12])=[S:11])[CH3:9].[CH:13]([SH:17])([CH2:15][CH3:16])[CH3:14]>O1CCCC1>[CH:13]([S:17][P:10]([CH2:8][CH3:9])([SH:12])=[S:11])([CH2:15][CH3:16])[CH3:14]
Reactant: CCP(=S)=S
Reactant: CCC(C)S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(C)SP(=S)(S)CC
Temperature: 25 °C

Procedure:
The triethylamine salt of S-(sec-butyl)ethylphosphonotrithioic acid was prepared as follows: 14.0 g (0.056 mole) of ethyl thionophosphine sulfide was dissolved in tetrahydrofuran; then 11.2 g (0.124 mole) of sec-butyl mercaptan was added, all at once. Then, 11.3 g (0.112 mole) triethylamine was added dropwise. The mixture was stirred at room temperature, then refluxed for 15 minutes. The solvent was removed in vacuo, leaving the acid salt (24.1 g, 68% of theoretical yield) as a semi-solid.