Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][CH:18]=[O:19])[C:15](=[O:20])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=O)C.[Na+].[CH3:22][SH:23]>O>[CH:18]([NH:17][C@@H:16]1[C:15](=[O:20])[N:10]2[C:11]([C:12]([OH:14])=[O:13])=[C:6]([CH2:5][S:23][CH3:22])[CH2:7][S:8][C@H:9]12)=[O:19]
Reactant: CS
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC=O)[C@H]2SC1
Agent: [Na+]
Solvent: O
Product: CSCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium 3-acetoxymethyl-7β-formamidoceph-3-em-4-carboxylate (3.22 g., 0.01 mole) in water (50 ml.) was treated with methanethiol (1.44 g., 0.03 mole) in a sealed glass tube at 70° for 2 hr. The contents of the tube were transferred to an open vessel and stirred at room temperature for 15 min. to allow the excess thiol to evaporate off. The solution was covered with ethyl acetate (50 ml.) and the pH of the aqueous layer adjusted to 1. The ethyl acetate layer was collected and combined with further ethyl acetate extracts (2 × 50 ml.) of the aqueous layer. The combined extract was washed successively with water (50 ml.) and brine (50 ml.), dried, and the solution evaporated, leaving impure 7β-formamido-3-methylthiomethylceph-3-em-4-carboxylic acid as a colourless foam (2.22 g.), which was dissolved in acetone (12 ml.) and ether (12 ml.), and a 10% w/v solution of sodium 2 -ethylhexanoate in acetone (12 ml.) was added. After refrigeration for 1 hr. the precipitate was collected by filtration, washed with acetone:ether (1:1, 2 × 10 ml.) and ether (2 × 20 ml.), and dried in vacuo giving sodium 7β-formamido-3-methylthiomethylceph-3-em-4-carboxylate as a colourless solid (1.69 g.), essentially homogeneous by thin-layer chromatography (trace of starting cephalosporanic acid), [α]D20 + 75.5° (c 1.00, water), λmax. (pH 6 buffer) 263 nm. (ε 7,760), νmax. (Nujol) 1760 (β-lactam), 1680, 1540 (amide), 1608 cm.-1 (CO2-), τ(D2O) 1.78 (1-proton singlet, CHO), 4.31 (1-proton doublet, J 4.5 Hz.: C-7H), 4.84 (1-proton doublet, J 4.5 Hz.: C-6 H) 6.20, 6.65 [two 1-proton doublets (branches or a quartet) J 17 Hz.: C-2 H2 ], 6.22, 6.69 [two 1-proton doublets (branches of a quartet), J 14 Hz.: C-3 CH2 ], 7.98 (3-proton singlet; SCH3)
Reaction SMILES: FC1C=CC=CC=1C1NC2C(=NC=NC=2)N=1.[F:17][C:18]1[C:26](F)=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: O=C(O)c1cccc(F)c1F
Agent: Fc1ccccc1-c1nc2ncncc2[nH]1
Product: O=C(O)c1ccccc1F
Yield: 45.7 %

Procedure:
Synthesized as described above for 8-(2-fluorophenyl)-purine, except that 2,3-difluorobenzoic acid was used instead of 2-fluorobenzoic acid (white powder, yield: 45.7%)
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([NH:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14](C(=O)C(F)(F)F)=[CH:13][CH:12]=2)[N:7]=1)=[O:4].ClCCl.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(N(CC)CC)C>[F:24][C:2]([F:1])([F:23])[C:3]([NH:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:7]=1)=[O:4]
Reactant: O=C(NC1=NN(c2ccc(C(=O)C(F)(F)F)cc2)CC1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1=NN(c2ccccc2)CC1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
A mixture of 5.0 g. of 3-amino-1-phenyl-2-pyrazoline (prepared as described in Example 8), 200 ml. of dichloromethane, 5.0 ml. of triethylamine and 7.0 ml. of trifluoroacetic anhydride is allowed to remain at room temperature for 30 minutes. The mixture is evaporated to dryness in vacuo, then water is added to separate a semi-solid. The solid is dissolved in dichloromethane. The solution is dried over anhydrous sodium sulfate, columnized and recrystallized as for Example 14 (B) to give 3.0 g. of the desired product as yellow-orange prisms, m.p. 163°-165° C.
Reaction SMILES: Br[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:15])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:17]1[CH:22]=[C:21]([C:2]2[C:7]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)=[N:6][NH:5][C:4](=[O:15])[CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2n[nH]c(=O)cc2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2n[nH]c(=O)cc2-c2cccc(Cl)c2)cc1
Temperature: 130 °C
Yield: 57.1 %

Procedure:
In a 10 mL heavy-walled sealed tube, a mixture of 5-bromo-6-p-tolylpyridazin-3(2H)-one (0.05 g, 0.189 mmol), 3-chlorophenylboronic acid (0.029 g, 0.189 mmol), Pd(Ph3P)4 (10.90 mg, 9.43 μmol) and K2CO3 (0.283 mL, 0.566 mmol) in dioxane (2 mL) was heated under microwave irradiation at 130° C. for 2 h. The reaction was purified by preparative HPLC to give the title compound (0.032 g). LCMS m/z=297.1 [M+H]+.
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].[Mg].C(Br)C.C#CC.[C:13]1([C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CCOCC.C1COCC1>[C:13]1([C:19]([C:1]#[C:2][CH3:3])([OH:24])[C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC#C[Mg]Br
Reactant: COC(=O)C(=O)c1ccccc1
Agent: C#CC
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: CCBr
Solvent: C1CCOC1
Product: CC#CC(O)(C(=O)OC)c1ccccc1
Reaction time: 24 h

Procedure:
1-Propynylmagnesium bromide (0.2 mole) was made from magnesium (4.8 g., 0.2 g. atom) ethyl bromide (21.8 g., 0.2 mole) and excess propyne gas in 400 ml. of THF. The Grignard reagent then was siphoned under nitrogen into an addition funnel and added dropwise over a 40 minute period to a cooled solution of methyl phenylglyoxylate (32.8 g., 0.2 mole) in 200 ml. of THF. A slight temperature rise took place. The reaction mixture was stirred for 24 hours, and then poured onto a slurry of ice and 25 ml. conc. HCl. Ether was added, and the layers were separated. Several more ether extracts were made and the organic extracts combined and dried. The volatile components were stripped subsequently in vacuo and the residue distilled to yield 13.1 g. (32%) of the product, b.p. 109°-12° (0.2 mm.). The oil solidified on standing and melted at 64°-65° after recrystallization from 20°-40° petroleum ether.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:16]P(OCC)(OCC)=O)=[N:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:5])C.[H-].[Na+].[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[C:34]3[N:35]([C:39]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[C:40]([CH:42]=O)[N:41]=3)[N:36]=[CH:37][CH:38]=2)[CH2:29][CH2:28]1>C1COCC1>[O:27]1[CH2:28][CH2:29][N:30]([C:33]2[C:34]3[N:35]([C:39]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[C:40](/[CH:42]=[CH:16]/[C:10]4[CH:9]=[CH:8][C:7]5[C:6]([C:4]([OH:3])=[O:5])=[CH:15][CH:14]=[CH:13][C:12]=5[N:11]=4)[N:41]=3)[N:36]=[CH:37][CH:38]=2)[CH2:31][CH2:32]1
Reactant: O=Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccccc1
Reactant: CCOC(=O)c1cccc2nc(CP(=O)(OCC)OCC)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1cccc2nc(/C=C/c3nc4c(N5CCOCC5)ccnn4c3-c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
A solution of compound 73d (119 mg, 0.339 mmol) in THF (6 mL) was treated with NaH (36.9 mg, 0.924 mmol) at 0° C. and the resulting mixture was allowed to warm to room temperature over 10 min. Compound 74a (95.0 mg, 0.308 mmol) was then added in one portion and the resultant mixture was heated to 55° C. for 1 h. The reaction was allowed to cool to rt, quenched with saturated sodium bicarbonate (2 mL) and extracted with DCM (10 mL). The DCM layer was separated, dried over Na2SO4, filtered, and concentrated, and the resultant residue was purified by flash column chromatography over silica gel (0-100% EtOAc/DCM) to afford compound 74b. Mass spectrum (LCMS, ESI pos.) Calcd. For C28H23N5O3 478.2 (M+H). found 478.1.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:19]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]4[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=4[N:20]=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[CH3:36][O:37][C:38]1[C:43]([O:44][CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])=[CH:42][C:41]([CH2:53][OH:54])=[C:40]([Sn](C)(C)C)[CH:39]=1>O1CCOCC1.CCOC(C)=O>[CH3:36][O:37][C:38]1[C:43]([O:44][CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])=[CH:42][C:41]([CH2:53][OH:54])=[C:40]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([C:19]4[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:22]5[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=5[N:20]=4)=[N:7][N:8]3[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=2)[CH:39]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c2ccc(I)cc21
Reactant: COc1cc([Sn](C)(C)C)c(CO)cc1OCOCC[Si](C)(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccc3c(-c4nc5ccccc5n4COCC[Si](C)(C)C)nn(COCC[Si](C)(C)C)c3c2)c(CO)cc1OCOCC[Si](C)(C)C
Yield: 60 %

Procedure:
6-Iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazol-2-yl}-1H-indazole [Example 24(a), step (v)] (300 mg, 0.48 mmol) and [4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-phenyl]-methanol (282 mg, 0.63 mmol) were stirred in dioxane (8 mL) under argon at 98° C. for 16 h. The reaction was allowed to cool and was diluted with EtOAc. Organics were washed with sat NaHCO3 and brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (20% EtOAc/hexanes) gave 224 mg (60%) of 6-[5-methoxy-2-hydroxymethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazol as a faint yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.70 (d, 1H, J=8.4 Hz), 7.89–7.92 (m, 1H), 7.63–7.66 (m, 2H), 7.34–7.41 (m, 4H), 6.91 (s, 1H), 6.29 (s, 2H), 5.83 (s, 2H), 5.36 (s, 2H), 4.55 (s, 2H), 3.78–3.92 (m, 5H), 3.59–3.70 (m, 4H), 0.83–1.04 (m, 6H), 0.03 (s, 9H), −0.04 (s, 9H), −0.13 (s, 9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7](S(C1C=CC=CC=1)(=O)=O)[CH:6]=[C:5]2[CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.[OH-].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[CH2:22][N:23]1[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cn(S(=O)(=O)c3ccccc3)c(=O)c3ccc(Br)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c[nH]c(=O)c3ccc(Br)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To a solution of tert-butyl 4-{[6-bromo-1-oxo-2-(phenylsulfonyl)-1,2-dihydroisoquinolin-4-yl]methyl}piperazine-1-carboxylate (Example 27a, 1.35 g) in THF (10 mL) was added sodium hydroxide (0.29 g) in water (5 mL). The reaction was stirred at room temperature for 2 h. The reaction was then heated to 50° C. for 2 h. The volatiles were removed under reduced pressure, and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous was extracted further with ethyl acetate (2×100 mL), and the combined organics dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was triturated with ethyl acetate to afford the subtitle compound as a white solid (0.29 g).
Reaction SMILES: CO[C:3](=[O:18])[CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7].[NH3:19]>CO>[C:3]([CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7])(=[O:18])[NH2:19]
Reactant: N
Reactant: COC(=O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Solvent: CO
Product: NC(=O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
[(5-Chloro-1H-indole-2-carbonyl)-amino]-acetic acid methyl ester (100 mg, 0.40 mmol) was added to a saturated solution of ammonia in methanol (ca. 3 mL) at 25° C. The suspension was sonicated for 1 hour and the resulting solution concentrated. The residue was triturated with ether/hexanes and dried. Yield 77 mg, 77%; HPLC (60/40) 2.78 minutes (98%); PBMS 252/254 (MH+, 100%);
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:25])=[C:20]([C:22](=[O:24])[CH3:23])[CH:21]=1>CN(C)C=O>[CH2:7]([O:25][C:19]1[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][C:20]=1[C:22](=[O:24])[CH3:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Cl)ccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
Potassium carbonate powder (2.9 g, 21.0 mmol) and benzyl bromide (2.3 g, 18.2 mmol) was added to a solution of 1-(5-chloro-2-hydroxyphenyl)-1-ethanone [compound (8-1)] (3.0 g, 17.6 mmol) in dimethylformamide (50 mL), and the mixture was stirred for 3 hours at 60° C. After cooling, ice-water was added to the resultant mixture, followed by extraction with ethyl acetate. The mixture was washed with aqueous sodium hydroxide (5%) and water, and dried over magnesium sulfate. The solvent was removed under reduced pressure, to thereby yield compound (9-1) as a colorless oily product (4.6 g, yield: 99.9%).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([CH:15]1[CH:39]=[C:38]2[C@:33]([CH3:41])([CH2:34][CH2:35][C:36](=[O:40])[CH2:37]2)[C@@H:32]2[C@@H:16]1[C@H:17]1[C@:29]([CH3:42])([CH2:30][CH2:31]2)[C@@H:20]([C@H:21]([CH3:28])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:19][CH2:18]1)[CH:13]=[CH2:14]>>[CH2:12]([CH:15]1[CH2:39][C:38]2[C@:33]([CH3:41])([CH2:34][CH2:35][C:36](=[O:40])[CH:37]=2)[C@@H:32]2[C@@H:16]1[C@H:17]1[C@:29]([CH3:42])([CH2:30][CH2:31]2)[C@@H:20]([C@H:21]([CH3:28])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:19][CH2:18]1)[CH:13]=[CH2:14]
Reactant: C=CCC1C=C2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@H]12
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCC1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@H]12

Procedure:
Following the general DBU catalyzed isomerization conditions of Example 5, compound 13 was analogously treated to yield the title compound 14.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:25]1([CH2:24][NH:1][C:2]2[N:10]=[C:9]3[C:5]([C:6]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[C:7]([C:11]4[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=4)[NH:8]3)=[CH:4][CH:3]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Fc1ccc(-c2[nH]c3nc(NCc4ccccc4)ccc3c2-c2ccncc2)cc1
Reaction time: 0.25 h

Procedure:
6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (100 mg, 0.329 mmol), benzaldehyde (100 ml, 0.987 mmol), and 1,2-dichloroethane (20 mL) were allowed to stir for 15 min followed by the addition of sodium triacetoxyborohydride (139 mg, 0.658 mmol) as a solid. After 16 h at 23° C., the reaction was partitioned between ethyl acetate (200 mL) and satd bicarbonate (80 mL). The organic layer was washed with brine (80 mL), and dried (Na2SO4). After concentration in vacuo, a portion of the residue was purified by preparative chromatography to afford 6-(phenylmethylamino)-3-(4-pyridyl)-2-(4-fluoro phenyl)-7-aza-indole (144):Mass Spectrum (CI) 395 (MH+).
Reaction SMILES: C([O:4][CH2:5][C:6]([Cl:8])=[O:7])(=O)C.Cl.Cl.[NH2:11][CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[N:20]=[C:21]([N:24]=[C:25]([NH2:31])[NH:26][CH2:27][CH2:28][O:29][CH3:30])[S:22][CH:23]=2)[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>ClCCl>[ClH:8].[NH2:31][C:25](=[N:24][C:21]1[S:22][CH:23]=[C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][NH:11][C:6](=[O:7])[CH2:5][OH:4])[CH:14]=2)[N:20]=1)[NH:26][CH2:27][CH2:28][O:29][CH3:30]
Reactant: COCCNC(N)=Nc1nc(-c2cccc(CN)c2)cs1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCNC(N)=Nc1nc(-c2cccc(CNC(=O)CO)c2)cs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.6 %

Procedure:
A solution of acetoxyacetyl chloride (1.08 g) in dichloromethane (10 ml) was added slowly to a suspension of 4-(3-aminomethylphenyl)-2-[[(amino)(2-methoxyethyl-amino)methylene]amino] thiazole dihydrochloride (2.5 g) and triethylamine (1.60 g) in dichloromethane (40 ml) with cooling on an ice bath. The mixture was stirred at room temperature for 1 day. The solvent was removed under reduced pressure. The residue was suspended in water (100 ml). The mixture was alkalified with an aqueous potassium carbonate solution and then extracted with a mixture of ethyl acetate (250 ml) and tetrahydrofuran (50 ml). The extract was dried with magnesium sulfate and then was evaporated in vacuo. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (20:1). The solvent was removed under reduced pressure. The residue was dissolved in methanolic ammonia (50 ml). The mixture was stirred with cooling on an ice-water bath for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in ethanol (50 ml) and 4N- dioxane solution of hydrogen chloride (10 ml) was added to the mixture. The mixture was stirred at room temperature for 4 hours. The resulting precipitate was collected by filtration. Recrystallization from ethanol afforded 2-[[(amino)(2-methoxyethylamino)methylene]amino]-4-(3-hydroxyacetamidomethylphenyl)thiazole hydrochloride (0.57 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1)[NH2:16]>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([NH:16][C:15]2[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:13]([F:12])[CH:14]=2)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(N)cc(F)c1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Solvent: ClCCl
Product: COc1cc(F)cc(NC(=O)c2c(Cl)ncnc2Cl)c1
Reaction time: 0.5 h
Yield: 51 %

Procedure:
4,6-Dichloropyrimidine-5-carbonyl chloride (590 mg, 2.79 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dissolved in dichloromethane (3 ml) and TEA (389 μl, 2.79 mmol) was added. To this solution, 3-fluoro-5-methoxyaniline (394 mg, 2.79 mmol) dissolved in 3 ml dichloromethane was added dropwise and the mixture was stirred for 30 min. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The crude (800 mg, 56% purity, 51% yield) was used in the next synthetic step without further purification.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1)(=O)=O.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31]>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH:31][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: NCc1cccc(Cl)c1
Solvent: CN(C)C=O
Product: Clc1ccc(-c2cnc(NCc3cccc(Cl)c3)nc2-c2ccc(Cl)cc2Cl)cc1
Temperature: 100 °C

Procedure:
To a 5 mL round bottom flask fitted with a stirrer bar and rubber septum was added 1 mL DMF and 2-methylsulfonyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (103 mg, 0.2 mmol) from Step A. Then 3-chlorobenzyl amine (2 eq, 50 μL, 0.4 mmol) was added vial syringe and the mixture heated at 100° C. for 4 h. HPLC/MS, showed that the starting material had been converted to the desired product. The product was extracted from 10 mL water with 20 mL ether, dried over MgSO4, filtered and the solvent removed under reduced pressure. Flash column chromatography on silica gel (eluted with 92/8 hexanes/ethyl acetate) afforded the desired product. HPLC/MS: m/e=476 (M+1); Rt=4.70 min; 1H-NMR 500 MHz (CDCl3): δ 5.46 (s, 2H), 7.08 (d, J=9 Hz, 2H), 7.31-7.4 (m, 5H), 7.41-7.53 (m, 4H), 9.00 (s, 1H).
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([CH:26]=[C:27]([N+:29]([O-])=O)[CH:28]=1)[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl.[Zn]>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([CH:26]=[C:27]([NH2:29])[CH:28]=1)[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)cc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1cc(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
2.52 g (38.5 mmol) Zn were suspended in 6 mL methylene chloride (dry, distilled), 0.9 mL (15.7 mmol) acetic acid were added and the suspension was cooled to 0° C. A solution of 0.7 g (1.93 mmol) nitrobenzoate 12 in 2 mL methylene chloride was added by syringe. After 2 h of stirring, TLC (hexanes/ethyl acetate, 7:3, Rf=0.4) indicated complete conversion of starting material. Zn was filtered off and the filtrate was concentrated, taken up in ethyl acetate and washed with aqueous NaHCO3 three times, then with brine. After drying with MgSO4 and evaporation, an orange-brown oil was obtained, which was purified by column chromatography (hexanes/ethyl acetate, 7:3) to afford 310 mg (48%) of a yellow oil. 1H NMR (CDCl3) δ 7.50-7.27 (m, 10H), 7.12 (dd, J1=1.3 Hz, J2=2.2 Hz, 1H), 7.02 (dd, J1=1.3 Hz, J2=2.2 Hz, 1H), 6.49 (t, J1=2.2 Hz, J2=2.2 Hz, 1H), 5.38 (s, 2H, PhCH2), 5.03 (s, 2H), 3.69 (s, 2H, PhCH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].CC[O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:7]([C:13]([OH:12])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:20]=[N:6]2)=[CH:8][CH:9]=1
Reactant: COc1cccc(N)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)c1cnc2cc(OC)ccc2c1O
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of m-methoxyaniline (35 g, 0.28 mol) and diethyl ethoxymethylene malonate (74 g, 0.34 mol) was stirred 2 h at 110° C. under reduce pressure. The mixture was heated at 240° C. under reduced pressure for an additional 2 h. The resulting solid was suspended in CH2Cl2, filtered off and washed with CH2Cl2 to yield 7-methoxy-4-hydroxy-3-ethoxycarbonylquinoline as a white solid.