Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:14](O)=[O:15])[C:5]1=[O:17])([CH3:3])[CH3:2].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:14]([Cl:20])=[O:15])[C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)n1c(=O)c(C(=O)O)cc2ccccc21
Solvent: Cc1ccccc1
Product: CC(C)n1c(=O)c(C(=O)Cl)cc2ccccc21

Procedure:
A solution of 3.88 g of 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid and 5.0 ml of thionyl chloride in 50 ml of toluene was stirred at 100° C. for 5 hours. After toluene was distilled off under vacuum, toluene was again added to the residue. The solvent was again distilled off under vacuum to give 4.22 g of 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1)=O.[Cl-].[F:24][C:25]1([F:32])[CH2:30][CH2:29][CH:28]([NH3+:31])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[BH4-].[Na+]>CO.O>[F:24][C:25]1([F:32])[CH2:30][CH2:29][CH:28]([NH:31][CH2:1][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][CH:7]=[C:8]3[O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=2)[CH2:27][CH2:26]1
Reactant: NC(=O)c1ccc(Oc2cccc3c(C=O)cccc23)nc1
Reactant: [NH3+]C1CCC(F)(F)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: O
Product: NC(=O)c1ccc(Oc2cccc3c(CNC4CCC(F)(F)CC4)cccc23)nc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 6-(5-formylnaphthalen-1-yloxy)nicotinamide (Preparation 35) (200 mg, 0.7 mmol) in MeOH (10 mL) was added 4,4-difluorocyclohexylammonium chloride (141 mg, 0.8 mmol), DIPEA (358 μl, 2.1 mmol) and 4 Å molecular sieves (200 mg). The mixture was stirred at 50° C. for 16 h, cooled to rt and NaBH4 (78 mg, 2.1 mmol) added. After 3 h water (1 mL) was added and the mixture filtered. Solvent was removed in vacuo and the residue purified by column chromatography (10% MeOH-EtOAc) to give the title compound: RT=2.40 min; m/z (ES+)=412.2 [M+H]+.
Reaction SMILES: [OH-].[K+].[CH3:3]N(N=O)C(N[N+]([O-])=O)=N.[CH2:13]([NH:20][C:21](=[O:25])/[CH:22]=[CH:23]/[CH3:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC([O-])=O.CC([O-])=O.[Pd+2].CCOCC>[CH2:13]([NH:20][C:21]([C@@H:22]1[CH2:24][C@H:23]1[CH3:3])=[O:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Reactant: C/C=C/C(=O)NCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Product: C[C@@H]1C[C@H]1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In an Erlenmeyer flask containing Et2O (300 mL) and aq. 40% KOH (111 mL) with vigorous stirring was added 1-methyl-3-nitro-1-nitrosoguanidine (11.1 g, 67 mmol) portionwise over 5 min. at rt. Upon complete addition stirring was ceased and the aq. layer frozen in a −78° bath. The ether layer was decanted into an Erlenmeyer with KOH pellets. The contents allowed to stand for 5 min., decanted into a third flask with KOH pellets and then poured onto a Et2O/THF solution (200 mL/50 mL) containing (2E)-N-benzylbut-2-enamide (3.0 g, 17.1 mmol from step A). Pd(OAc)2 (180 mg, 0.9 mmol) was subsequently added and the reaction allowed to warm to rt and stir for 1 h. Nitrogen was bubbled through the reaction for 10 min. The mixture was washed with H2O (150 mL). The organic layer was isolated and subsequently dried over Na2SO4. Solvent removal and purification by flash chromatography on SiO2 (EtOAc/hexanes) gave N-benzyl-trans-2-methylcyclopropanecarboxamide: 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 5H), 5.81 (br s, 1H), 4.43 (dd, J=5.6, 2.4 Hz, 2H), 1.37 (m, 1H), 1.17 (m, 1H), 1.07 (d, J=6.0 Hz, 3H), 1.04 (overlapping m, 1H), 0.56 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:22]2[N:21]=[C:20]([CH3:23])[C:19]([CH3:24])=[N:18][C:17]=2[C:16]([C:25]([OH:27])=O)=[CH:15][CH:14]=1.[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(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:25]([C:16]3[C:17]4[N:18]=[C:19]([CH3:24])[C:20]([CH3:23])=[N:21][C:22]=4[C:13]([C:3]4[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[Cl:12])=[CH:14][CH:15]=3)=[O:27])=[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: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3nc(C)c(C)nc23)c1Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nc(C)c(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,3-dimethyl-quinoxaline-5-carboxylic acid (Step 122.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), and stirring the reaction mixture 18 h at rt. Title compound: ESI-MS: 595.0 [M+H]+; tR=3.86 min (System 1); TLC: Rf=0.15 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][SH:13].[Na]>C(O)C>[CH3:12][S:13][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: CS
Agent: [Na]
Solvent: CCO
Product: CSc1cccc(F)c1[N+](=O)[O-]
Reaction time: 2 h
Yield: 84.8 %

Procedure:
2,6-Difluoronitrobenzene (1.0 g, 6.3 mmol) was stirred in ethanol (10 mL) and treated with sodium methylmercaptan (0.44 g, 6.3 mmol) in several portions over 5 minutes. After stirring for 2 hours the mixture was evaporated and chromatographed on silica gel (70% hexane:30% ethyl acetate) to give 2-methylmercapto-6-fluoronitrobenzene (approximately 1.0 g), which was reduced in ethanol (30 mL) using 5% palladium on carbon (0.3 g) and hydrogen (50 psi) for 2 hours. The catalyst was removed by filtration through celite and the solvent evaporated to give 2-fluoro-6-(methylthio)benzenamine (0.69 g).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=2)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=3)=[N:6][C:5]([C:3]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(-c2cncc(F)c2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A mixture of 7-benzyl-1-(5-fluoro-pyridin-3-yl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.074 mmol), glycine (740 mg, 9.9 mmol) and NaOMe solution (15 mL, 7.4 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 3-4. The organic layer was dried over MgSO4 and concentrated. The crude was chromatographed (20-100% EtOAc/hexanes+2% AcOH) to give 19 mg of the title compound as a white solid. MS: (+) m/z 448.95 (M+1).
Reaction SMILES: C([C:8]([NH2:13])(O)[CH:9]([OH:11])[CH3:10])(OC(C)(C)C)=O.[OH:14][C:15]([CH:17]([C:19]1[CH:32]=[CH:31][CH:30]=[C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:20]=1)[CH3:18])=[O:16].[ClH:33].C(OCC)(=O)C.CCCCCC>ClCCl>[NH2:13][CH2:8][CH:9]([OH:11])[CH2:10][OH:14].[ClH:33].[OH:16][C:15]([CH:17]([C:19]1[CH:32]=[CH:31][CH:30]=[C:21]([C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:20]=1)[CH3:18])=[O:14]
Reactant: CC(O)C(N)(O)C(=O)OC(C)(C)C
Agent: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: NCC(O)CO
Reaction time: 3 h

Procedure:
The Boc-amino-1,2-propanediol-ketoprofen (1.76 mmol) obtained above was dissolved in dichloromethane (1 ml), and under ice-cooling, 4 N hydrochloric acid/ethyl acetate (4 ml) was added thereto, followed by stirring for 3 hours. Hexane was added to the reaction solution, and the thus formed white precipitate was dried under reduced pressure to give the titled compound (1.029 g, yield 97%). The structure was identified by 1H-NMR (CDCl3).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=O)=[CH:3][CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.[OH-].[Na+]>C1(C)C(C)=CC=CC=1.P(Cl)(Cl)(Cl)=O>[CH3:19][C:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:17]3[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)NCCc2ccccc2Cl)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc(C2=NCCc3c(Cl)cccc32)cc1
Yield: 44.3 %

Procedure:
1-(p-Toluoylamino)-2-(2-chlorophenyl)ethane (70 g) was dissolved in 700 ml of xylene and 320 ml of phosphorus oxychloride, and while the solution was heated with stirring, 240 g of phosphorus pentoxide was added. The mixture was heated under reflux for 4 hours. Water was added to the reaction mixture. The aqueous layer was made weakly alkaline with an aqueous solution of sodium hydroxide, extracted with benzene, washed in water, and dried. The solvent was distilled off, and the residue was recrystallized from benzene to afford 29 g of 1-(4-methylphenyl)-5-chloro-3,4-dihydroisoquinoline as colorless needles.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([O:10][CH3:9])[CH:12]=2)[CH:3]=1
Reactant: COc1cccc(CCl)c1
Reactant: Oc1ccc(Br)cc1
Product: COc1cccc(Cc2cc(Br)ccc2O)c1

Procedure:
Alkylation of 4-bromophenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-bromo-2-(3'-methoxybenzyl)phenol. This material was converted to compound 75, mp 97-101.5° C., and compound 76, mp 102-106° C., by the procedure similar to that in Example 18 method B.
Reaction SMILES: [N:1](OCCCC)=[O:2].[CH3:8][C:9]1[C:14]([CH3:15])=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:11][C:10]=1[Br:20].CC(C)([O-])C.[K+].O>CN(C)C=O.C(O)(=O)C>[Br:20][C:10]1[C:9]([CH3:8])=[C:14]([C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=1)[CH:15]=[N:1][OH:2]
Reactant: Cc1c(Br)ccc(S(C)(=O)=O)c1C
Reactant: CCCCON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Br)ccc(S(C)(=O)=O)c1C=NO
Temperature: 0 °C

Procedure:
A solution of 2.1 g (20 mmol) of n-butyl nitrite (97%) pure and 4 g (15 mmol) of 2,3-dimethyl-4-methylsulfonylbromobenzene in 50 ml of dimethylformamide is cooled to from −55 to −60° C., and a solution of 2.8 g (25 mmol) of potassium tert-butoxide in 35 ml of dimethylformamide is added dropwise at this temperature, over a period of 20 minutes. The reaction is monitored by HPLC. For work-up, initially 10 ml of water are added, and the pH is subsequently adjusted to 5-6 using approximately 9 ml of glacial acetic acid. The reaction mixture is subsequently poured into 100 ml of ice-water, and the aqueous phase is extracted with methylene chloride. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. This gives 3.6 g of an oily crude product (90% pure according to HPLC) which can be purified by recrystallization from toluene.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH2:7][N:6]([CH3:20])[CH2:5][C:4]=2[N:3]=1.N(CC)CC.[CH2:26]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:27][C:28]#[CH:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.[Cu]I.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>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]2[CH2:7][N:6]([CH3:20])[CH2:5][C:4]3[N:3]=[C:2]([C:29]#[C:28][CH2:27][CH2:26][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:11]=[CH:10][C:9]2=3)=[CH:13][CH:14]=1
Reactant: COc1ccc(C2CN(C)Cc3nc(Cl)ccc32)cc1
Reactant: C#CCCN1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1ccc(C2CN(C)Cc3nc(C#CCCN4CCCCC4)ccc32)cc1
Temperature: 25 °C
Yield: 32.1 %

Procedure:
A flask containing a mixture of 2-chloro-5-(4-methoxy-phenyl)-7-methyl-5,6,7,8-tetrahydro-[1,7]naphthyridine (0.080 g, 0.28 mmol), Et2NH (1.0 mL), 1-but-3-ynyl-piperidine (0.077 g, 0.56 mmol), CuI (5.3 mg, 27.8 umol), PPh3 (36 mg, 0.14 mmol), and Pd(PPh3)2Cl2 (0.020 g, 0.028 mmol) in DMF (0.5 mL) was evacuated and back-filled with N2 (3×). The mixture was heated at 105 C for 18 h, then was cooled to rt, diluted with satd. aq. NaHCO3, and extracted with DCM. The combined organic layers were washed with H2O, dried, and concentrated. The residue was purified (SiO2; 0-6% 2 M NH3 in MeOH/DCM) to give the title compound (35 mg, 33%). MS (ESI): mass calcd. for C25H31N3O, 389.25; m/z found, 390.6 [M+H]+. 1H NMR (CDCl3): 7.15-7.08 (m, 2H), 7.06 (d, J=8.7, 2H), 6.83 (d, J=8.7, 2H), 4.23-4.17 (m, 1H), 3.91-3.85 (m, 1H), 3.79 (s, 3H), 3.66-3.59 (m, 1H), 3.05-2.99 (m, 1H), 2.76-2.62 (m, 4H), 2.56-2.46 (m, 5H), 2.45 (s, 3H), 1.68-1.58 (m, 4H), 1.49-1.40 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:8]([S:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)=[CH:7][C:5]([NH2:6])=[C:4]([N+:20]([O-])=O)[CH:3]=1.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:6])=[CH:7][C:8]=1[S:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]=[CH:15]2
Reactant: Nc1cc(Sc2cccc3cnccc23)c(F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(F)c(Sc2cccc3cnccc23)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
4-Fluoro-5-(5-isoquinolylsulfanyl)-2-nitroaniline 1.60 g (5.1 mmol) was dissolved in concentrated hydrochloric acid 30 ml, stannous chloride dihydrate 4.10 g (18.2 mmol) was added, and the mixture was stirred for 2 hours at room temperature. After 50% sodium hydroxide was added, the resulting alkaline solution was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate-n-hexane to obtain 4-fluoro-5-(5-isoquinolylsulfanyl)-1,2-benzenediamine 1.00 g (69.1%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[N:8]=1.[CH3:17][N:18]1[C:23](=[O:24])[C:22]2[C:25]([S:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)=[C:26]([CH:28]=[O:29])[S:27][C:21]=2[N:20]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:19]1=[O:40].[Li]C1C=CC=CN=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[OH:29][CH:28]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[N:8]=1)[C:26]1[S:27][C:21]2[N:20]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:19](=[O:40])[N:18]([CH3:17])[C:23](=[O:24])[C:22]=2[C:25]=1[S:30][C:31]1[S:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccs3)c(C=O)sc21
Reactant: FC(F)(F)c1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Li]c1ccccn1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccs3)c(C(O)c3cccc(C(F)(F)F)n3)sc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium in hexane (2.5M, 369 μl) was added dropwise to a solution of 2-bromo-6-trifluoromethylpyridine in tetrahydrofuran (8 ml) at −78° C. and the resulting solution was stirred for 1 h. 1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-5-(2-thienylthio)-thieno[2,3-d]pyrimidine-6-carboxaldehyde (0.25 g) (Example 50, step c) in tetrahydrofuran (2 ml) was added dropwise to the lithio pyridine solution. The reaction was stirred for 3 hours at −78° C. then saturated ammonium chloride solution was added (20 ml) and the reaction was left to warm to room temperature. The reaction was extracted thrice with ethyl acetate (50 ml), then the organic phases were washed with brine and dried over magnesium sulfate, filtered and evaporated to leave a brown oil. The residue was purified by chromatography (1:4, ethyl acetate: isohexane) to give the title compound as a pale brown oil (0.03 g).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>ClC1C=CC=CC=1Cl.[Cu]>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:11]1[C:12]2[NH:13][C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[O:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: Ic1ccccn1
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: Clc1ccccc1Cl
Product: c1ccc(-c2cccc3c2Nc2ccccc2O3)nc1
Yield: 91 %

Procedure:
To start with, 1.73 g of phenoxazine, 2.90 g of 2-iodopyridine, 5.24 g of potassium carbonate, 1.2 g of copper powder, and 0.25 g of 18-crown-6-ether were mixed with the use of 20 ml of ortho-dichlorobenzene as a solvent, followed by reflux under a nitrogen atmosphere for 8 hours. After that, copper and inorganic salt were removed, and then column purification using a dichloromethane solvent was performed to give a ligand ppx (1-(2-pyridyl)phenoxazine) (white powder; yield: 91%). A summary of the synthesis scheme is shown in the following (a-2).
Reaction SMILES: C([O-])(=O)C.[NH4+].C([BH3-])#[N:7].[Na+].[CH3:10][C:11]([CH3:26])=[CH:12][CH2:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][C:21](=O)[CH3:22])=[CH:17][CH:16]=1>CO>[CH3:10][C:11]([CH3:26])=[CH:12][CH2:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH:21]([NH2:7])[CH3:22])=[CH:17][CH:16]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)COc1ccc(OCC=C(C)C)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)=CCOc1ccc(OCC(C)N)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Ammonium acetate (3.29 g, 42.7 mmol), sodium cyanoborohydride (0.20 g, 3.0 mmol) and 3A molecular sieves are added to the above phenoxyacetone (1.0 g, 4.3 mmol) in 20 ml of anhydrous methanol under N2 and at RT. The reaction is stirred at RT for 4 days. The methanol is removed by rotoevaporation, and ether and water are added to the residue, followed by 10% NaOH. The mixture is extracted with ether (3×), and the combined organic layers are washed with water until neutral, dried and filtered and the solvent evaporated off to give 2-[4-(3-methyl-2-butenoxy)phenoxy]-1-methylethylamine.
Reaction SMILES: [S:1]([O-:5])([O-])(=[O:3])=[O:2].[Ca+2].S(=O)(=O)=O.[Cl:11][C:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13].ClC([O-])=O>C(Cl)Cl>[Cl:11][C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:1]([OH:5])(=[O:3])=[O:2])=[CH:17][CH:16]=1)=[O:13]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=S(=O)([O-])[O-]
Agent: O=C([O-])Cl
Agent: O=S(=O)=O
Agent: [Ca+2]
Solvent: ClCCl
Product: O=C(Cl)Oc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a 100 mL 3-necked round bottom flask equipped with a magnetic stirrer, addition funnel topped with a drying tube containing calcium sulfate was added 35 mLs of methylene chloride. The reaction solvent was cooled with an ice water bath. To the flask was added 2.8 grams (0.035 mole) of liquid sulfur trioxide. Thereupon the reaction solution became a very pale clear yellow liquid. The ice water bath cooled reaction vessel was then charged with 5.48 grams (0.035 mole) of phenyl chloroformate added dropwise so as to control the reaction exotherm. When approximately half of the chloroformate had been added, a white precipitate began to form. Upon completion of the addition, the reaction mixture was allowed to warm to room temperature. After six hours at room temperature, a 95%+ conversion was noted by proton nmr analysis. Solvent was removed under vacuum and the remaining white to slightly off-white crystalline solid was used as is for the condensation reaction. The following spectroscopic data was obtained for this material:
Reaction SMILES: Cl[CH2:2][C:3]1[N+:12]([O-:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:25][CH2:24][O:23][C:8]=3[CH:9]=2)[N:4]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.CN(C=O)C>CO>[N:26]1([CH2:2][C:3]2[N+:12]([O-:13])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:10]3[C:5](=[CH:6][C:7]4[O:25][CH2:24][O:23][C:8]=4[CH:9]=3)[N:4]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: [O-][n+]1c(CCl)nc2cc3c(cc2c1-c1ccc2c(c1)OCO2)OCO3
Reactant: C1CCNC1
Solvent: CO
Solvent: CN(C)C=O
Product: [O-][n+]1c(CN2CCCC2)nc2cc3c(cc2c1-c1ccc2c(c1)OCO2)OCO3
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline-3-oxide (200 mg, 0.55 mmol), in MeOH (5 mL), was added pyrrolidine (0.4 mL). The mixture was stirred at 65° C. for 1.5 h. DMF (6 mL) was added and the heating was continued at 60° C. for 15 h. After cooling, the separated solid was collected by filtration, washed with hexane, and air dried to give the title compound as off white solid (175 mg). The crude product was purified by column chromatography on silica gel (CH2Cl2:MeOH 95:5); mp 194-202° C. 1H NMR (CDCl3) 7.39 (s, 1H), 6.90-7.06 (m, 4H), 6.78 (s 1H), 6.11 (s, 2H), 6.08 (s, 2H), 4.25 (s, 2H), 2.87 (bs, 4H), 1.91 (bs, 4H).
Reaction SMILES: Cl([O-])=[O:2].[Na+].[C:5]([NH:8][C@@H:9]1[C@@H:14]([CH2:15][CH:16]=[O:17])[CH2:13][C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:11][C@H:10]1[O:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])(=[O:7])[CH3:6].CC(=CC)C>OP([O-])(O)=O.[K+].C(O)(C)(C)C>[C:5]([NH:8][C@@H:9]1[C@@H:14]([CH2:15][C:16]([OH:2])=[O:17])[CH2:13][C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:11][C@H:10]1[O:22][CH:23]([CH2:24][CH3:25])[CH2:26][CH3:27])(=[O:7])[CH3:6]
Reactant: [O-][Cl+][O-]
Reactant: CCC(CC)O[C@@H]1C=C(C(=O)OC)C[C@H](CC=O)[C@H]1NC(C)=O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCC(CC)O[C@@H]1C=C(C(=O)OC)C[C@H](CC(=O)O)[C@H]1NC(C)=O
Reaction time: 16 h
Yield: 85.2 %

Procedure:
Sodium chlorite (commercial 80%, 16 mg, 0.142 mmol) in 2 mL of KH2PO4 buffer (pH 3-4) was added dropwise to a room temperature solution of Example 7A (36 mg, 0.110 mmol) and 2-methyl-2-butene (118 μL, 1.10 mmol) in tert-butyl alcohol (15 mL). After stirring for 16 hours, the reaction mixture was concentrated. The concentrate was purified by flash chromatography on silica gel using acetic acid/ethyl acetate (1/5) to afford 32 mg (84%) of the desired product as a white solid.
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11]C)=[O:10])=[CH:5][CH:4]=1.[OH-:13].[Na+].Cl>O>[CH3:2][N:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][C:4]1=[O:13]
Reactant: COC(=O)c1cc[n+](C)cc1
Reactant: [OH-]
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: Cn1ccc(C(=O)O)cc1=O
Temperature: 55 °C
Reaction time: 4 h

Procedure:
A solution of N-methyl-4-methoxycarbonylpyridinium iodide (2.00 g, 7.16 mmol) in water (10 mL) at room temperature was treated sequentially with 14M sodium hydroxide (1.0 mL) and 1.8M K3Fe(CN)6 (1.5 mL), stirred for 4 hours, treated again with 1.8M K3Fe(CN)6 once per hour for 4 hours, heated at 55° C. for one hour, cooled to room temperature, and treated with 6M HCl to pH 3. The precipitate was collected, washed with ether and dried under vacuum to provide 1.00 g of the desired product.