Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13]([OH:15])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:37])C(=O)C1>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][C:20]=1[Cl:37])\[C:13]([OH:15])=[O:14])([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)c(Cl)s1
Yield: 91.8 %

Procedure:
A solution of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (70 g, 147 mmol) and NCS (23.50 g, 176 mmol) in N,N-Dimethylformamide (DMF) (735 mL) was stirred at 40° C. for 2.5 h. The reaction was quenched by addition of H2O (2 L), EtOAc (1 L) and 5% aq. sodium thiosulfate soln (400 mL). The organic layer was separated, and washed with H2O (2×), brine, dried and evaporated to afford (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetic acid (69 g, 91% purity, 135 mmol, 92% yield) as a light yellow foaming solid. LCMS: (M+H)+: 464.2
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Br.Br.[C:22]12[CH2:29][NH:28][CH2:27][C:26]=1[CH2:25][NH:24][CH2:23]2.C(N(C(C)C)CC)(C)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:24]4[CH2:25][C:26]5[CH2:27][NH:28][CH2:29][C:22]=5[CH2:23]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: C1NCC2=C1CNC2
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2cc(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Yield: 76.5 %

Procedure:
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (4.4 g) and 3,7-diazabicyclo[3.3.0] oct-1(5)-ene dihydrobromide (4.2 g) were added to diisopropyl ethylamine (11.6 ml) in acetonitrile (120 ml) and refluxed for 7 hours. The produced precipitate was filtered, washed with acetonitrile (100 ml), water (50 ml), ethanol (50 ml) and them ethyl ether (50 ml) to give the title compound (4.2 g, yield 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])=[C:20]([CH2:30][CH3:31])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.N1(C2C=CN=CC=2)CCCC1.[C:43]([O:47][C:48]([NH:50][CH2:51][C:52](O)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44].C(N=C=NC(C)C)(C)C.O.NN>C(Cl)Cl>[C:43]([O:47][C:48]([NH:50][CH2:51][C:52]([O:29][C:26]([CH3:27])([CH3:28])[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([N:13]2[C:14](=[O:17])[C:15]3[S:16][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:9][C:10]=3[N:11]=[CH:12]2)=[CH:19][C:20]=1[CH2:30][CH3:31])=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: CCc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: NN
Agent: c1cc(N2CCCC2)ccn1
Solvent: O
Solvent: ClCCl
Product: CCc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)OC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.1 %

Procedure:
To a solution of 6-(4-chlorophenyl)-3-(3-ethyl-4-(2-hydroxy-2-methylpropoxy)-phenyl)thieno[3,2-d]pyrimidin-4(3H)-one (0.96 g, 2.11 mmol), 4-pyrrolidinopyridine (0.31 g, 2.11 mmol) and N-(tert-butoxycarbonyl)glycine (1.11 g, 6.33 mmol) in 20 mL of CH2Cl2 heated at reflux was added diisopropylcarbodiimide (0.98 mL; 6.33 mmol) over 3 h via syringe pump. The suspension was heated at reflux for 1 h and additional N-(tert-butoxycarbonyl)glycine (0.55 g, 3.17 mmol) was added followed by diisopropylcarbodiimide (0.55 mL, 3.17 mmol) over 2 hrs via syringe pump. The suspension heated at reflux for 1 h and cooled to rt. Hydrazine monohydrate (0.34 mL, 7.01 mmol) was added and the suspension stirred at rt for 2 h. The suspension was cooled to 0° C., filtered and the filtrate washed with cold, 1N HCl, cold, dilute NaHCO3 solution, dried over anhydrous MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAc/Hexanes, 0:100 to 1:1 gradient) to afford 1.37 g (100%) of the title compound as an off-white solid. 1H NMR (CDCl3) δ 1.24 (t, 3H), 1.45 (s, 9H), 1.64 (s, 6H), 2.68-2.73 (m, 2H), 3.85 (d, J=4.95 Hz, 2H), 4.18 (s, 2H), 4.98 (br s, 1H), 6.92 (d, J=9.35 Hz, 1H), 7.20-7.22 (m, 2H), 7.44 (d, J=8.79 Hz, 2H), 7.53 (s, 1H), 7.66 (d, J=8.25 Hz, 2H), 8.13 (s, 1H); 13C NMR (CDCl3) δ 13.68, 23.39, 23.67, 28.28, 42.87, 72.72, 79.86, 81.86, 111.48, 120.82, 123.25, 125.42, 127.62, 129.42, 129.67, 131.54, 134.25, 135.59, 148.29, 151.50, 155.58, 156.69, 156.92, 157.37, 169.47; HPLC (Method #1) 4.80 min retention time; LCMS (ES): m/z 612 [M+H]+.
Reaction SMILES: CC([O:5][C:6](=[O:19])[CH2:7][N:8]1[CH2:16][CH2:15][CH2:14][NH:13][C:12]2[C:11](=[O:17])[C:10](=[O:18])[C:9]1=2)(C)C.[OH-].[Na+:21]>>[OH2:5].[Na+:21].[O:17]=[C:11]1[C:10](=[O:18])[C:9]2[N:8]([CH2:7][C:6]([O-:19])=[O:5])[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=2
Reactant: CC(C)(C)OC(=O)CN1CCCNc2c1c(=O)c2=O
Agent: [Na+]
Agent: [OH-]
Product: O
Product: O=C([O-])CN1CCCNc2c1c(=O)c2=O
Reaction time: 8 h
Yield: 132.9 %

Procedure:
An ethanolic (86 mL) solution of (8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)acetic acid 1,1-dimethylethyl ester (2.29 g, 8.60 mmol) was treated at room temperature with 2.5N sodium hydroxide solution (3.5 mL, 8.7 mmol) and left stirring overnight. The suspension was filtered, washing with ethyl acetate to give a solid which was recrystallized from methanol/water/isopropanol (final volume 50 mL) to afford (8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)acetic acid sodium salt hydrate (1.43 g, 66%, mp 280°-300° C. dec); MS (-FAB): 231 (M-H, 37), 209 (M-Na, 100); 1H NMR (DMSO 1 drop of DCl, 400 MHz): δ 4.40 (s, 2H), 3.36-3.25 (m, 4H), 1.89 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[F:10][C:11]([F:26])([F:25])[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)[OH:13].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]([O:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[C:11]([F:10])([F:26])[F:25])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: OC(c1ccccc1-n1ccnc1)C(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(Cl)cc(OC(c2ccccc2-n2ccnc2)C(F)(F)F)n1
Temperature: 42.5 °C
Reaction time: 6 h
Yield: 99.9 %

Procedure:
2-Amino-4,6-dichloro pyrimidine (0.107 g, 0.65 mmol), 2,2,2-trifluoro-1-(2-imidazol-1-yl-phenyl)-ethanol (0.157 g, 0.65 mmol), and NaH (0.03 g, 0.78 mmol) were added to anhydrous THF (10 ml) under nitrogen. The reaction was stirred at 40-45° C. for 6 h, and was then cooled to room temperature, and quenched with water (0.2 ml). The reaction mixture was concentrated to give crude 4-chloro-6-[2,2,2-trifluoro-1-(2-imidazol-1-yl-phenyl)-ethoxy]-pyrimidin-2-ylamine (0.24 g, >90% pure by LCMS), which was directly used in the following step.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[Cl:10][C:11]1[CH:16]=[CH:15]C(B(O)O)=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:28]1(C)C=CC=CC=1>>[CH3:28][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:2][C:3]=1[C:9]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1
Reactant: Cc1cccc(C)c1Br
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1ccc(C)c(-c2ccc(Cl)cc2)c1
Yield: 95 %

Procedure:
2-Bromo-m-xylene (77 mg, 0.42 mmol) reacted with 4-chlorophenylboronic acid (94 mg, 0.60 mmol) using 1/2 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and K3PO4 (254 mg, 1.20 mmol) in toluene at 100° C. to give the title compound (85 mg, 95%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 7.27 (d, 2H, J=8.0 Hz), 7.14 (d, 2H, J=8.0 Hz), 7.06 (d, 1H, J=7.6 Hz), 6.98 (bs, 1H), 6.92 (s, 1H), 2.25 (s, 3H), 2.11 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 140.44, 135.30,132.66, 132.04, 130.46, 130.33, 128.23, 128.18, 20.88, 19.88. GC/MS(EI): m/z 216 (M+), 181, 166, 89.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Cl[C:24]1[N:25]=[C:26]([S:32][CH3:33])[N:27]=[N:28][C:29]=1[C:30]#[N:31]>O1CCOCC1>[CH3:33][S:32][C:26]1[N:27]=[N:28][C:29]([C:30]#[N:31])=[C:24]([N:11]2[CH2:10][CH:9]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)[N:25]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: CSc1nnc(C#N)c(Cl)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nnc(C#N)c(N2CC=C(c3ccccc3)CC2)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
A solution of 130 mg (0.66 mmol) of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride in 5 ml of dioxane was treated at room temperature with 0.23 ml (1.32 mmol) of N-ethyl-diisopropylamine and, thereupon, with 112 mg (0.60 mmol) of crude 5-chloro-3-methylsulfanyl-[1,2,4]triazine-6-carbonitrile. The reaction mixture was stirred at 50° C. during 18 hours. For the working-up, the solution was evaporated under reduced pressure and the residue was chromatographed on silica gel with a 2:1 mixture of hexane and ethylacetate as the eluent. There were obtained 120 mg (0.34 mmol, 64.5% of theory) of 3-methylsulfanyl-5-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-[1,2,4]triazine-6-carbonitrile in the form of an orange powder; MS: [M+H]+=310.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-])=O.[H][H]>[O-]S([O-])(=O)=O.[Ba+2].C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: CN(C)C(=O)Nc1ccc(OCCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Product: CN(C)C(=O)Nc1ccc(OCCc2ccccc2)c(N)c1

Procedure:
A mixture of 3-[3-nitro-4-(phenethyloxy)phenyl]-1,1-dimethylurea (5.8 g; 0.0175 mol), 5% palladium in BaSO4 catalyst (6.0 g) and 95% ethyl alcohol (100 ml) is shaken in a hydrogen atmosphere at 2.8 kg/cm2 pressure (40 psig) for 18 hours. The mixture is then filtered and the ethanol removed under vacuum. The residue is washed with toluene to afford the title compound, m.p. 125°-126° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14](Cl)=[O:15].[OH:22][CH2:23][CH2:24][CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27].C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([O:22][CH2:23][CH2:24][CH2:25][C:26](=[O:27])[N:28]([CH3:30])[CH3:29])=[O:15]
Reactant: CN(C)C(=O)CCCO
Reactant: CC(OCc1ccc2ccccc2c1)(C(=O)Cl)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CCCOC(=O)C(C)(OCc1ccc2ccccc2c1)C(F)(F)F
Reaction time: 48 h
Yield: 34.5 %

Procedure:
A solution of (±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionyl chloride (3.0 g.) in tetrahydrofuran (70 ml.) is added, dropwise at 0° C., to a stirred solution of 4-hydroxy-N,N-dimethylbutyramide (1.20 g.) and triethylamine (2.1 g.) in tetrahydrofuran (35 ml.). The mixture is stored for 2 days. The solid is filtered off and washed with ether, and the filtrate and washings are evaporated. The residue is dissolved in ether and the solution is washed with water, 0.4 N aqueous sodium hydroxide, and water, dried with magnesium sulphate, and evaporated. The residue is crystallised from a mixture of light petroleum (b.p. 40°-60° C.) and ether to give (±)-3-dimethylcarbamoylpropyl 2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate (1.3 g.) m.p. 42°-43° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][S:15][C:10]=2[CH:9]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:19])=O>C(#N)C.CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][S:15][C:10]=2[CH:9]=1)[C:5]([Cl:19])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CON=C(C(=O)O)c1cc2sccc2s1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CON=C(C(=O)Cl)c1cc2sccc2s1

Procedure:
A solution of 400 mg of α-methoxyimino-α-(thieno[3,2-b]thien-2-yl)acetic acid in 50 ml of acetonitrile containing 15 ml of oxalyl chloride and two drops of N,N-dimethylformamide was stirred at 0° C. for two hours. The reaction mixture was concentrated to dryness by evaporation under reduced pressure to provide α-methoxyimino-α-(thieno[3,2-b]thien-2-yl)acetyl chloride as an oil. The oil was dissolved in 10 ml of fresh acetonitrile and added to a stirred acetonitrile solution of 707 mg of 7-amino-3-methyl-3-cephem-4-carboxylic acid silylated with 2.56 g of bis(trimethylsilyl)trifluoroacetamide (BSTFA). The reaction mixture was stirred at 25° C. for sixteen hours. The reaction mixture was concentrated to dryness to provide an oil which was sonicated for fifteen minutes with 300 ml of saturated aqueous sodium bicarbonate. The mixture was acidified to pH 2.3 by addition of 1N hydrochloric acid. The acid layer was extracted several times with ethyl acetate, and the combined extracts were dried and the solvent was removed by evaporation to provide 970 mg of 7-α-methoxyimino-α-(thieno[3,2-b]thien-2-yl)acetamido-3-methyl-3-cephem-4-carboxylic acid.
Reaction SMILES: C(OC([N:6]=[S:7]([CH3:35])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[S:29][CH:30]=[N:31][N:32]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:33][CH3:34])[CH:10]=1)=[O:8])=O)C.[O-]CC.[Na+].CCCCCC.ClCCl.CO>CO>[CH3:34][O:33][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:17]=1[O:16][CH2:15][C:11]1[CH:10]=[C:9]([S:7]([CH3:35])(=[NH:6])=[O:8])[CH:14]=[CH:13][CH:12]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:27][C:28]1[S:29][CH:30]=[N:31][N:32]=1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4nncs4)c3cc2OC)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CO
Product: COc1cc2c(Nc3nncs3)ncnc2cc1OCc1cccc(S(C)(=N)=O)c1
Yield: 35 %

Procedure:
According to GWP 6, the reaction of (RS)-N-(ethoxycarbonyl)-S-methyl-S-[3-({[6-methoxy-4-(1,3,4-thiadiazol-2-ylamino)quinazolin-7-yl]oxy}methyl)phenyl]-sulphoximide (37 mg, 0.072 mmol) with sodium ethoxide (25 mg, 0.39 mmol) and chromatographic purification (silica gel, hexane, dichloromethane/methanol: 0→15% methanol) gives the desired product in 35% yield (11 mg).
Reaction SMILES: C([O:4][C:5]1[N:6]=[C:7]([CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=2)(=O)C.N.[Li+].[OH-].Cl[CH2:35][C:36]1[C:37]([NH:48][CH2:49][CH3:50])=[N:38][C:39]2[C:44]([CH:45]=1)=[CH:43][C:42]([O:46][CH3:47])=[CH:41][CH:40]=2>C(Cl)Cl.CO>[CH2:49]([NH:48][C:37]1[C:36]([CH2:35][C:14]2[C:13]3[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:15][CH3:16])[CH:12]=3)[C:7]([CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[N:6][C:5]=2[OH:4])=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([O:46][CH3:47])[CH:43]=2)[N:38]=1)[CH3:50]
Reactant: CCNc1nc2ccc(OC)cc2cc1CCl
Reactant: COc1cc2cc(OC(C)=O)nc(CN3C(=O)c4ccccc4C3=O)c2cc1OC
Agent: N
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(CN2C(=O)c3ccccc3C2=O)c2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-((1,3-dioxoisoindolin-2-yl)methyl)-6,7-dimethoxyisoquinolin-3-yl acetate SIL 32166 (297 mg, 0.73 mmol) in dry CH2Cl2 (9 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added a 7 N NH3 solution in MeOH (1 mL) and the reaction mixture was stirred for 4 h at RT then concentrated to dryness at 40° C. under vacuum. The solid was taken up in THF (7 mL) and transferred in a 20 mL microwave vial equipped with a magnetic stirrer before addition of a 2 N aq. LiOH solution (0.37 mL, 0.74 mmol) and 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine SLA 28166 free base (240 mg, 0.96 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (80 mL) and the organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) followed by a second purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) gave 2-((4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-3-hydroxy-6,7-dimethoxyisoquinolin-1-yl)methyl)isoindoline-1,3-dione CCH 42006-1 as a yellow oil (75 mg, 32%).
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH2:13][NH:14][CH3:15])([CH3:3])[CH3:2].Cl.C[C:18]1(C)[O:23][C:22]2[CH:24]=[C:25]([CH:28]=[CH:29][C:30]([OH:32])=O)[CH:26]=[N:27][C:21]=2[NH:20][CH2:19]1.[OH:34]N1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH2:13][N:14]([CH3:15])[C:30](=[O:32])/[CH:29]=[CH:28]/[C:25]1[CH:26]=[N:27][C:21]2[NH:20][C:19](=[O:34])[CH2:18][O:23][C:22]=2[CH:24]=1)([CH3:3])[CH3:2]
Reactant: CNCc1oc2ccccc2c1C(C)C
Reactant: On1nnc2ccccc21
Reactant: CC1(C)CNc2ncc(C=CC(=O)O)cc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OCC(=O)N3)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.8 %

Procedure:
To a solution of (3-isopropylbenzofuran-2-yl)-N-methylmethanamine (115 mg, 0.57 mmol) in DMF (5 mL) were added in sequential order 3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid hydrochloride (118 mg, 0.51 mmol), 1-hydroxybenzotriazole (77 mg, 0.57 mmol), diisopropylethylamine (289 uL, 1.54 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (109 mg, 0.57 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water was added with rapid stirring. The product was extracted with ethyl acetate (3×10 mL), dried over sodium sulfate, filtered and concentrated to give a light brown solid (14 mg, 7%): 1H NMR (400 MHz, CD3OD) δ 11.42 (s, 1H), 8.17-8.16 (m, 1H), 7.89-7.86 (m, 1H), 7.74-7.72 (m, 2H), 7.24-7.30 (m, 2H), 7.22-7.17 (m, 2H), 4.97 (s, 2H), 4.78 (s, 2H), 3.15 (s, 3H), 3.10-3.14 (m, 1H), 1.34 (s, 6H); MS (ESI) m/e 406 (C23H23N3O4+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4].C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29][NH:30][CH3:31]>O1CCOCC1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29][N:30]([CH3:31])[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: CNCc1ccc(Cl)cc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(CC(=O)c1cccc([N+](=O)[O-])c1)Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-bromo-1-(3-nitrophenyl)ethanone (2 g, 8.23 mmol, 1.00 equiv), triethylamine (3.4 g, 4.00 equiv), (2,4-dichlorophenyl)-N-methylmethanamine (1.9 g, 10.05 mmol, 1.20 equiv), 1,4-dioxane (50 mL). The resulting solution was stirred for 2 h at room temperature at which time it was judged to be complete by LCMS. The mixture was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100˜1:50). This resulted in 1.5 g (50%) of 2-((2,4-dichlorobenzyl)(methyl)amino)-1-(3-nitrophenyl)ethanone as a yellow solid.
Reaction SMILES: [C:1]([C@@H:6]([C@H:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[OH:9])[OH:7])([O:3][CH2:4][CH3:5])=[O:2].O=[CH:16][C:17]1[CH:26]=[CH:25][C:23]([OH:24])=[C:19]([O:20][CH2:21][CH3:22])[CH:18]=1.C1(C)C=CC=CC=1.O>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[CH2:21]([O:20][C:19]1[CH:18]=[C:17]([CH:16]2[O:9][C@@H:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C@H:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[O:7]2)[CH:26]=[CH:25][C:23]=1[OH:24])[CH3:22]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CCOC(=O)[C@@H]1OC(c2ccc(O)c(OCC)c2)O[C@H]1C(=O)OCC
Yield: 33.9 %

Procedure:
A mixture of diethyl L-tartrate (309 g, 1.5 mol), ethyl vanillin (166 g, 1 mol), toluene (2 L) and p-toluenesulfonic acid (5 g, 0.026 mol) was heated at 115°-116° C. for 24 hours under a nitrogen atmosphere. During the reaction, water was removed by azeotropic distillation via a Dean-Stark trap. The mixture was washed sequentially with saturated sodium bicarbonate solution (500 mL), brine (2×1 L) and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the solid obtained was recrystallized from isopropanol to provide 120 g (34% yield) of (4R,5R)-2-(3-ethoxy-4-hydroxy-phenyl)4,5-dicarboethoxy-1,3-dioxolane, mp 78°-80° C., [α]D25 -38° (c,1.0, methanol). 1H-HMR (CDCl3)δ 7.17 (1H,d,J=1.8 Hz), 7.06 (1H,dd,J=1.8 Hz and 8.10 Hz), 6.91 (1H,d,J= 8.2 Hz), 6.07 (1H,s), 5.83 (1H,s), 4.91, (1H,d,J=4.0 Hz), 4.80 (1H,d,J=4.0 Hz), 4.37-4.25 (4H, 2 q, overlapping, J=7.2 Hz), 4.15 (2H,q,J=7.0 Hz), 1.45 (3H,t,J=7.0 Hz), 1.38-1.29 (6H,2 t, overlapping J=7.2 Hz). IR (KBr) 3390, 2980, 2930, 1735, 1600 cm-1. MS m/e (% abundance) 354 (55), 326 (3), 281 (40), 182 (85), 167 (85), 154 (100), 137 (70), 110 (30), 93 (10), 81 (10), 53 (5).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>C(O)(C)C>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[NH2:14])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: NCc1ccccc1N
Reactant: CSc1ncnc2cc(N)ncc12
Solvent: CC(C)O
Product: Nc1cc2ncnc(NCc3ccccc3N)c2cn1
Yield: 47.1 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (136 mg, 0.71 mmol) (described in a previous experimental) and 2-aminobenzylamine (1.70 g, 13.8 mmol) in isopropanol (5 mL) is stirred at reflux for 1 h, and the resulting product is chromatographed on silica gel (7-20% EtOH/EtOAc) and alumina (6-10% EtOH/CHCl3) to give 7-amino-4-(2-aminobenzylamino)pyrido[4,3-d]pyrimidine (89 mg, 47%) as a white solid. 1H NMR (DMSO) δ 9.08 (1H, s), 8.68 (1H, t, J=5.8 Hz), 8.26 (1H, s), 7.05 (1H, d, J=7.4 Hz), 6.96 (1H, t, J=7.6 Hz), 6.63 (1H, d, J=7.9 Hz), 6.51 (1H, t, J=7.4 Hz), 6.46 (2H, brs), 6.35 (1H, s), 5.20 (2 H, brs), 4.56 (2H, d, J=5.8 Hz).