Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:32]([O:36][C:37](=[O:43])[C@@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1)([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[C:32]([O:36][C:37](=[O:43])[C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[C:11](=[O:13])[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(CC(C(=O)O)c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 0.01 mole sample of 3-benzoyl-2-(phenyl)propionic acid is dissolved in tetrahydrofuran and 0.01 mole of N,N-carbonyldiimidazole added. After stirring 3 hours at room temperature, 0.01 mole of L-proline t-butyl ester is added. After 24 hours the solvent is removed and 1-[3-benzoyl-2-(phenyl)-propionyl]-L-proline t-butyl ester isolated. The preceding compound is reacted with trifluoroacetic acid to remove the t-butyl group. Separation of isomers A and B is carried out as described for Example 69. Reaction of the isomers with bromine is acetic acid and reaction of the 1-[3-bromo-3-benzoyl-2-(phenyl)propionyl]-L-proline isomers with sodium thioacetate in acetonitrile as for Example 69 gives the products of the example. The product from isomer A is separated by chromatography to give [S-(R*,R*)] and [S-(R*,S*)]-1-[3-acetylthio-3-benzoyl-2-(phenyl)propionyl]-L-proline.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[Cl:23]C(OC(Cl)C)=O>ClCCCl>[ClH:23].[N+:20]([C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:10][CH2:9][CH:8]([N:5]3[CH2:6][CH2:7][NH:2][CH2:3][CH2:4]3)[CH2:13][CH2:12]2)=[CH:19][CH:18]=1)([O-:22])=[O:21]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CN1CCN(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)CC1
Solvent: ClCCCl
Product: Cl
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCNCC3)CC2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a mixture of 1-methyl-4-[1-(4-nitrophenyl)piperidin-4-yl]piperazine (4.84 g) and 1,2-dichloroethane (50 mL) was added 1-chloroethyl chloroformate (2.2 mL), followed by stirring at 90° C. for 3 hours. The solvent was evaporated under reduced pressure and then methanol (85 mL) was added thereto, followed by heating and refluxing for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was washed with ethyl acetate to obtain 1-[1-(4-nitrophenyl)piperidin-4-yl]piperazine monohydrochloride (3.74 g) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]=[O:13])=[N:11][C:4]=2[NH:3]1.[OH:14]OS([O-])=O.[K+]>CN(C=O)C>[O:1]=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=[O:13])=[N:11][C:4]=2[NH:3]1
Reactant: O=S([O-])OO
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CSc2ccc(C(=O)O)nc2N1
Reaction time: 1.5 h
Yield: 77.9 %

Procedure:
This acid was prepared from 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (890 mg) by oxidation with Oxone (potassium peroxymonosulphate) (3.1 g) in a DMF solution (50 mL). After 1.5 hours at room temperature, dilution with water (50 mL) filtration and drying in vacuo afforded the acid as a white solid (750 mg, 77%).
Reaction SMILES: [OH-:1].[K+].[OH:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:7]1[CH2:16][C:15](=O)[C:14]2[C:9](=[CH:10][C:11]([O:19][CH2:20][CH2:21][Br:22])=[CH:12][C:13]=2[OH:18])[O:8]1.O.Cl>C(Cl)Cl.CO>[OH:18][C:13]1[CH:12]=[C:11]([O:19][CH2:20][CH2:21][Br:22])[CH:10]=[C:9]([OH:8])[C:14]=1[CH:15]=[CH:16][C:7]([C:6]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:4]([OH:3])[CH:5]=1)=[O:1]
Reactant: [OH-]
Reactant: COc1ccc(C2CC(=O)c3c(O)cc(OCCBr)cc3O2)cc1O
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)C=Cc2c(O)cc(OCCBr)cc2O)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Ten ml of 5% KOH is added to 400 mg (1.00 mmole) of 3',5-dihydroxy-4'-methoxy-7-bromoethoxy-flavanone giving a bright yellow solution which is stirred under argon at ambient temperature for 2 hours. The reaction mixture is then poured into 100 ml of water, acidified with 10% HCl, and extracted immediately with ethyl acetate (2 × 25 ml). The combined extracts are washed with dilute NaHCO3 (1 × 25ml), dried over MgSO4 and concentrated yielding 0.51 g of a partially crystalline orange oil. Tlc (silica gel F-254, CH2Cl2 --CH3OH 95:5), indicates the reaction to have proceeded nearly quantitatively showing only the product (Rf =0.28) and a barely observable spot for starting material (Rf =0.73). Preparative tlc on silica gel PF-254, eluting with CH2Cl2 --CH3OH 95:5, yielded 302 mg (75%) of the chalcone as a yellow solid. Recrystallization from hexaneethyl acetate gives orange clusters having mp 158°-162°C and spectra consistent with material 7b.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14](Cl)[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCO>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([S:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(c(Cl)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: CCOC(=O)CS
Solvent: CCO
Product: CCOC(=O)CSc1nc(C)cc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Yield: 49 %

Procedure:
A solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (200 mg, 0.55 mmol) in EtOH (10 mL) was added ethyl 2-mercaptoacetate (0.12 mL, 1.10 mmol) and TEA (0.23 mL, 1.65 mmol). The reaction was heated at reflux for 24 h. The reaction mixture was cooled, concentrated in vacuo, diluted with water and extracted is with EtOAc. The combined organic extracts were washed with water, brine, and dried over Na2SO4. Solvents were removed in vacuo and the residue was purified by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) to provide ethyl [(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetate (120 mg, 49%): LCMS RT: 3.07 min, MH+: 446.2.
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:20]1[CH:25]=[CH:24][CH:23]=[C:22](I)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[C:33]1([CH3:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O>[CH:4]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:1]=[CH:2][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:35]2[CH:36]=[CH:37][C:38]3[C:18]4[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=4)[C:6]4[C:39](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:33]=3[CH:34]=2)[CH:21]=1
Reactant: Cc1ccccc1
Reactant: Ic1cccc(I)c1
Reactant: c1ccc2c(c1)c1ccccc1c1ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: c1cc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc(-c2ccc3c4ccccc4c4ccccc4c3c2)c1
Temperature: 87 °C
Reaction time: 24 h

Procedure:
1.23 g (3.5 mmol) of the triphenylene moronic ester from the previous step, 0.5 g (1.5 mmol) of 1,3-diiodobenzene, 1.0 g (7.5 mmol) of potassium carbonate, 30 mL of toluene, and 10 mL of water was mixed in a 250 mL three-neck flask. The system was purged by nitrogen for 10 min before adding 0.05 g of Pd(PPh3)4. The mixture was then heated up to 87° C. with vigorous stirring. After 24 hr, to the mixture was added 200 mL of methanol. The precipitate was collected by filtration. The solid was washed with copious amount of methanol, then hexanes. The solid was then recrystallized from 80 ml of xylenes. Final purification of the product involved subliming the material at 250° C. 0.35 g product was collected as white needle crystals.
Reaction SMILES: B(F)(F)F.CCOCC.ClCCl.C[SiH](C)C.[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30](=[O:60])[C@@H:31]([O:57][CH2:58][CH3:59])[C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]([CH3:56])[C:48](=[O:55])[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:41]=2)=[CH:36][CH:35]=1)O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30](=[O:60])[C@@H:31]([O:57][CH2:58][CH3:59])[CH2:32][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]([CH3:56])[C:48](=[O:55])[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:41]=2)=[CH:36][CH:35]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1
Agent: C[SiH](C)C
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CCO[C@@H](Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
320 μl (2.6 mmol) of boron trifluoride etherate and 5 ml of dichloromethane are introduced into a three-necked flask under a stream of nitrogen. At 0° C., 800 μl (5 mmol) of trimethylsilyl hydride are added dropwise, followed by portionwise addition of 380 mg (0.64 mmol) of N-{4′-[(1R,2S)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-ethoxy-1-hydroxy-3-oxopropyl]biphenyl-3-ylmethyl}-N-methylbenzamide. After one hour at room temperature, the mixture is heated at 50° C. for 20 hours. The reaction medium is poured into water and extracted with ethyl acetate, and the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (70/30). 280 mg (76%) of the expected product are obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])=[N:4][N:3]=1.[C:23]([O-:26])([O-])=[O:24].[K+].[K+].[CH:29]1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>CS(C)=O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:29][O:26][C:23]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])=[N:4][N:3]=1)=[O:24]
Reactant: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)c1nnc(Cc2c(Cl)cncc2Cl)c2ccc(OC)cc12
Temperature: 50 °C
Yield: 726.4 %

Procedure:
A suspension of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (9.7 g, 27 mmoles), prepared as described in example 45, in DMSO/CH3OH (80/40 ml) was added with K2CO3 (7.4 g, 54 mmoles), palladium acetate (0.31 g, 1.4 mmoles) and 1,3-bis(diphenylphosphine)propane (0.75 g, 1.82 mmoles). The mixture was placed in autoclave under CO atmosphere (8 bar) and heated at 50° C. After 4 hours the mixture was poured into water (10 volumes) and extracted four times with ethyl acetate. The organic phase was washed with aqueous NaCl and discoloured with charcoal, filtered and dried to give a solid which was flash chromatographed (eluent: petrolatum/ethyl acetate 1:1) to give 5 g of the title compound (yield: 49%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=1[F:43]>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=3[F:43])[OH:25])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)c1nc2c(c(C3=CCOCC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@@H](O)c1ccc(C(F)(F)F)cc1F)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-(3,6-dihydro-2H-pyran-4-yl)-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 1-bromo-2-fluoro-4-(trifluoromethyl)benzene.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].C([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:11]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])=O.N1C=CC=[CH:35][CH:34]=1>N1CCCCC1>[CH2:34]([C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:10](/[CH:1]=[CH:2]\[C:3]([OH:5])=[O:4])=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:12]2[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH3:35]
Reactant: CCOC(=O)c1c(C=O)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: c1ccncc1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(/C=C\C(=O)O)c2c(CC)cccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
Malonic acid (106 mg) and piperidine (1 drop) were added to a solution of ethyl 3-formyl-N-(3,4-dichlorobenzyl)indole-2-carboxylate (315 mg) in pyridine (5 ml) and the reaction stirred at 100° C. overnight. The reaction was concentrated in vacuo and the residue dissolved in ethyl acetate (30 ml), washed with HCl (2M, 30 ml) and water (30 ml), dried (MgSO4) and concentrated in vacuo to give the crude product which was triturated with a mixture of dichloromethane, ethyl acetate and hexane to give the product as a tan coloured solid (68 mg, 19%); NMR d (CD3SOCD3) 1.25 (t, 3H), 4.35 (q, 2H), 5.80 (s, 2H), 6.55 (d, 1H), 6.90 (m, 1H), 7.25-7.45 (m, 3H), 7.50 (m, 1H), 7.60 (m, 1H), 8.05 (m, 1H), 8.35 (d, 1H) 12.24 (s, 1H); M/(−) 416.4 (M−H+).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](/[C:9](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)/[C:10]([O:12][CH3:13])=[O:11])=[O:8])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].O>ClCCCl>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:8])[CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[C:4]=2[CH:3]=1
Reactant: COC(=O)/C(=C\c1ccc(Cl)c(Cl)c1)C(=O)c1ccc(Br)s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)C1C(=O)c2sc(Br)cc2C1c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
A mixture of methyl (2Z)-2-[(5-bromo-2-thienyl)carbonyl]-3-(3,4-dichlorophenyl)acrylate (36.64 g, 87.22 mmol) and aluminum trichloride (14.0 g, 105 mmol) in 1,2-dichloroethane (687.2 mL) was heated at 80° C. under argon overnight. The mixture was then cooled to rt and water (20.4 mL) was added. The mixture was stirred for 30 min and then dryloaded on silica gel. Purified on two ISCO columns, 400 g, EtOAc in hex, 0-80% to afford the product as a yellow solid (31.6 g, 81.3%). LCMS: (AA) ES−: 417, 419. 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=8.3 Hz, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.02-6.94 (m, 2H), 4.88 (d, J=3.5 Hz, 1H), 3.83 (s, 3H), 3.76 (d, J=3.5 Hz, 1H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.I[CH2:24][CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11](=[O:22])[N:10]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:8]=2[N:9]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
To a suspension of NaH (60% in mineral oil, 36 mg) in 8 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (205 mg, 0.67 mmol). The mixture was heated at 60° C. for 20 minutes resulting in a clear solution. 1-Iodo-2-methylpropane (110 μL, 0.94 mmol) was added, and the solution was stirred at 50° C. for 30 minutes. An additional amount of 1-iodo-2-methylpropane (40 μL, 0.34 mmol) was added, and the solution was stirred at 50° C. for 40 minutes, then cooled to room temperature and poured onto 40 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The gummy residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was purified by flash chromatography, eluting with 1:1 hexane:ethyl acetate to provide 123 mg (51%) of 2-amino-6-(2,6-dichlorophenyl)-8-isobutyl-8H-pyrido[2,3-d]pyrimidin-7-one; mp 193-195° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[S:23]([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)([O:26][CH3:27])(=[O:25])=[O:24]>>[S:23]([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)([O-:26])(=[O:25])=[O:24].[CH3:27][P+:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1
Reactant: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: Cc1ccc([P+](C)(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Yield: 62 %

Procedure:
A mixture of 2.38 g (7.82 mmol) of tris(4-methylphenyl)phosphine and 1.53 g (8.22 mmol) of methyl tosylate were allowed to react for 1 hr at 130° C. A total of 2.38 g (4.85 mmol, 62.0%) of product was obtained, which was further purified by recrystallization from 97:3 toluene-ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](O)([CH3:17])[CH3:16])=[CH:4][CH:3]=1.CS(O)(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:15]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1
Reactant: CC(C)(O)c1ccccc1Nc1ccc(Cl)cc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
30.3 g (116 mmol) of 2-[2-(4-chlorophenylamino)phenyl]propan-2-ol are dissolved in 700 ml of degassed toluene, a suspension of 93 g of polyphosphoric acid and 61.7 g of methanesulfonic acid is added, and the mixture is stirred at room temperature for 1 h and heated at 50° C. for 1 h. The batch is cooled, added to ice and extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. Filtration of the crude product through silica gel with heptane/ethyl acetate (20:1) gives 25.1 g (89%) of 2-chloro-9,9-dimethyl-9,10-dihydroacridine as pale-yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1.C(N(CC)CC)C.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27].O>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Reactant: NCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cnc2cc(Br)cnc2c1NCCCO
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
To a solution of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine (22.53 g, 78.10 g) in dichloromethane (260 mL) at room temperature was added triethylamine (14.2 mL, 102 mmol). The solution was cooled to 0° C., and 3-amino-1-propanol (6.57 mL, 85.9 mmol) was added. The solution was stirred for 20 minutes at room temperature and then was concentrated under reduced pressure to yield a yellow solid. Water (250 mL) was added to the solid and the mixture was sonicated for 10 minutes. The solid was isolated by filtration, washed with water, and dried at 70° C. under vacuum to afford 22.60 g of 3-[(7-bromo-3-nitro[1,5]naphthyridin-4-yl)amino]propan-1-ol as a yellow powder.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.[N:35]1([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)CC>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:38]3[CH2:37][CH2:36][N:35]([C:41]4[CH:42]=[CH:43][C:44]([C:45]#[N:46])=[CH:47][CH:48]=4)[CH2:40][CH2:39]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][S:15][CH2:16][C@@H:8]12
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 26.9 %

Procedure:
(R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (80.0 mg, 0.318 mmol) was suspended in propionitrile (0.8 mL) and (cyanomethyl)trimethylphosphonium iodide (93.0 mg, 0.382 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (167 ul, 0.955 mmol). To the stirred mixture was then added 4-(piperazin-1-yl)benzonitrile (59.6 mg, 0.318 mmol). The reaction was heated to 90° C. with stirring for 16 h. The reaction was cooled to room temperature and left to sit 48 h. The precipitate was filtered off, washed with ethanol (5 mL) and dried in vacuum to afford the title compound (36.0 mg, 26.9%) as a white solid. 1H NMR (CHLOROFORM-d) δ (ppm): 8.26 (br. s., 1H), 7.79 (d, J=1.8 Hz, 1H), 7.44-7.60 (m, 2H), 6.96 (br. s., 1H), 6.76-6.91 (m, 2H), 5.05 (dt, J=13.6, 2.7 Hz, 1H), 4.43 (dd, J=10.7, 3.2 Hz, 1H), 3.27-3.63 (m, 6H), 3.15 (td, J=12.8, 2.3 Hz, 1H), 3.00 (td, J=12.8, 2.7 Hz, 1H), 2.77-2.93 (m, 2H), 2.59 (br. s., 4H), 2.34-2.45 (m, 1H). [M+H] calc'd for C22H24N6OS, 421. found, 421.
Reaction SMILES: Cl(O)(=O)(=O)=O.[OH2:6].O.O.O.[N+]([O-])([O-])=O.[Tl+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl.COCCOC>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([C:32]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:6])=[O:31])=[CH:28][CH:29]=1
Reactant: O=C(Cc1ccccc1)c1ccc(Br)cc1
Reactant: O
Agent: O=[N+]([O-])[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [Tl+3]
Solvent: ClCCl
Solvent: COCCOC
Product: O=C(C(=O)c1ccc(Br)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
Perchloric acid (250 mL), water (250 mL), ethylene glycol dimethyl ether (glyme) (500 mL), thallium (III) nitrate trihydrate (222.0 g, 0.5 mol) and 4-bromodeoxybenzoin (68.75 g, 0.25 mol) are charged to a 2-liter round bottom 3-necked flask equipped with a reflux condenser and a mechanical stirrer. The reaction mixture is heated under nitrogen to reflux for 6 hours. After cooling to ambient temperature, methylene chloride (500 mL) is added. The resulting bilayer is decanted off the precipitated Tl(I) salts formed. The layers are separated and the organic layer is washed with water, saturated aqueous NaHCO3 and brine, followed by recrystallization of the resulting solid from 2-propanol gives the title compound.