Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([F:35])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:36])[CH:8]=1)[CH3:2].C(OC(=O)C)(=[O:39])C.N1[CH:49]=[CH:48]C=CC=1>CN(C)C1C=CN=CC=1>[C:1]([N:3]([CH2:48][CH3:49])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([F:35])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:36])[CH:8]=1)(=[O:39])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCNCCOc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)OCC)c(F)c3)c2)c(C)c1
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Product: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OCCN(CC)C(C)=O)cc3C)c2)cc1F
Temperature: 25 °C
Reaction time: 62 h
Yield: 85 %

Procedure:
A mixture of ethyl 3-[4-({4′-[2-(ethylamino)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methoxy)-2-fluorophenyl]propanoate (0.27 g, 0.55 mmol), 4-dimethylaminopyridine (7 mg, 55 μmol), acetic anhydride (0.10 mL, 1.09 mmol) and pyridine (5.4 mL) was stirred at room temperature for 62 hrs. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-ethyl acetate) to give the title compound (0.25 g, yield 85%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32](O)=[O:33]>C1(C)C=CC=CC=1>[CH:32]([NH:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][CH2:23][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)=[CH:30][CH:29]=1)=[O:33]
Reactant: O=CO
Reactant: Nc1ccc(CCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Solvent: Cc1ccccc1
Product: O=CNc1ccc(CCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Yield: 97.7 %

Procedure:
The 4-[2-(3,4-dibenzyloxyphenyl)ethyl]benzenamine (4.5 g, 11 mmole) is dissolved in toluene (75 ml) containing formic acid (0.51 g, 11 mmole) and refluxed for two hours. The reaction mixture is evaporated to dryness, and the residue is recrystallized from toluene to afford 4.7 g (97%) of N-formyl-4-[2-(3,4-dibenyloxyphenyl)ethyl]benzeneamine, mp 119°-122° C.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[CH2:29][CH3:30])[NH2:25].Cl.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>CO.CCOC(C)=O>[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[CH2:29][CH3:30])[NH:25][C:2]1[N:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[CH2:29][CH3:30])[NH:25][C:2]1[N:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COc1ccc(Cc2cnc(Cl)c3cccnc23)cn1
Reactant: CCc1ccc(N)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: CCc1ccc(Nc2ncc(Cc3ccc(O)nc3)c3ncccc23)cc1Br
Product: CCc1ccc(Nc2ncc(Cc3ccc(OC)nc3)c3ncccc23)cc1Br
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Under a N2 atmosphere, 241 mg (0.84 mmol) of 5-chloro-8-[(6-methoxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine in 4 ml of methanol are mixed with 252 mg (1.26 mmol) of 3-bromo-4-ethyl-aniline (Ex. 9) and 0.21 ml of 4 N HCl/dioxane and stirred for 16 h at 80° C. The cooled reaction mixture is taken up with diluted Na2CO3 solution and EtOAc. The water phase is separated and extracted twice with EtOAc. The organic phases are dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2, toluene/EtOAc 2:1→EtOAc/acetone/EtOH 4:4:1→acetone/EtOH 9:1) and crystallisation from hexane yield 5-(3-bromo-4-ethyl-anilino)-8-[(6-methoxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine 37a (m.p. 142-146° C.; FAB-MS: (M+H)+=449/451; HPLC(gradient20-100) tRef=10.9) and 5-(3-bromo-4-ethyl-anilino)-8-[(6-hydroxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine 37b (m.p. 262-265° C.; FAB-MS: (M+H)+=435/437; HPLC(gradient20-100) tRef=9.3).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:14][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+]=[N-].[ClH:17].[H][H]>[Pd].C(O)C>[ClH:17].[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:14][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1ccc(CN=[N+]=[N-])cc1O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(CN)cc1O
Yield: 71 %

Procedure:
Palladium on carbon (0.5 g, 10% [w/w]) was added to a 1 L hydrogenation flask under a nitrogen atmosphere. The crude ethyl 4-azidomethylsalicylate was dissolved in ethanol (200 mL) and transferred to the hydrogenation flask. Concentrated aqueous hydrochloric acid (2 mL) was then added, and the flask was affixed to the Parr hydrogenator. The reaction mixture was shaken under 35 psi of hydrogen for 4 hours at room temperature. The mixture was then filtered through Celite to remove the catalyst, and the filtrate was evaporated to dryness to afford an off-white solid. Finally, this solid was crystallized from EtOH to afford 3.1 g (71% yield) of ethyl 4-aminomethylsalicylate hydrochloride (m.p. 240°-241° C.).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[CH:9][C:8]=1[F:20])=[O:6])[CH2:2][CH3:3].[C:21]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[CH2:1]([NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH3:19])([CH3:18])[C:15]([O:17][CH3:21])=[O:16])=[CH:9][C:8]=1[F:20])=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)c1ccc(NC(C)(C)C(=O)O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCCNC(=O)c1ccc(NC(C)(C)C(=O)OC)cc1F
Temperature: 55 °C
Yield: 76.3 %

Procedure:
The title compound was prepared according to General Method 5. A solution of 2-(4-(propylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid (1.0 g, 3.54 mmol) and K2CO3 (1.0 g, 7.2 mmol) in DMF (7 mL) was stirred at RT for 10 minutes. Methyl iodide (0.8 g, 5.6 mmol) was added and heated at 55° C. for 4 h. The solvent was removed and reaction mixture was poured in water, extracted with ethyl acetate, dried over Na2SO4, concentrated and purified with column chromatography to obtain 800 mg of methyl 2-(4-(propylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoate.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[F:12][C@@H:13]1[CH2:17][NH:16][C@H:15]([C:18]#[N:19])[CH2:14]1.C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>ClCCl.O>[Cl:27][CH2:28][C:29]([N:16]1[CH2:17][C@@H:13]([F:12])[CH2:14][C@H:15]1[C:18]#[N:19])=[O:30]
Reactant: O=C(Cl)CCl
Reactant: N#C[C@@H]1C[C@H](F)CN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl
Yield: 94 %

Procedure:
A solution of step 3 intermediate (10 g, 32.89 mmol) and triethylamine (4.32 g, 42.77 mmol) in dichloromethane (200 ml) was added drop wise to a stirred and cooled (0° C.) solution of chloroacetyl chloride (4.81 g, 32.95 mmol) in dichloromethane (50 ml) over a period of 10 min. The mixture was stirred at the same temperature for 2 h and diluted with dichloromethane (100 ml) and water (100 ml) under stirring. The layers were separated. The organic layer was washed with water (2×50 ml), brine (50 ml) and dried (Na2SO4). The residue obtained after evaporation of the solvent was triturated with diethyl ether to give 5.89 g (94%) of the product as an off-white solid, IR (KBr) 2924, 2241, 1678, 1407, 1281, 1225, 1076, 1051, 958 cm−1; 1H NMR (CDCl3, 300 MHz) δ 2.26-2.48 (m, 1H), 2.66-2.80 (m, 1H), 4.06 (s, 2H), 3.81-4.29 (m, 2H), 4.95 (d, J=9.6 Hz, 0.8H, rotomer), 5.38 (brd, J=51.3 Hz, 0.2H, rotomer) 5.46 (d, J=9.0 Hz, 0.2H, rotomer), 5.46 (dt, J=44.4, 3.3 Hz, 0.8H, rotomer).
Reaction SMILES: C([O:4][C@H:5]1[CH:10]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:9][C@H:8]2[C@H:17]3[C@H:27]([CH2:28][CH2:29][C@:6]12[CH3:7])[C@:25]1([CH3:26])[C@H:20]([CH2:21][C@@H:22]([CH3:31])[C:23](=O)[CH2:24]1)[CH2:19][CH2:18]3)(=O)C.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C(O)=O>[CH3:31][C@H:22]1[C@@H:23]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:24][C@@:25]2([CH3:26])[C@@H:20]([CH2:19][CH2:18][C@@H:17]3[C@@H:27]2[CH2:28][CH2:29][C@@:6]2([CH3:7])[C@H:8]3[CH2:9][C@H:10]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C@@H:5]2[OH:4])[CH2:21]1
Reactant: CC(=O)O[C@H]1C(N2CCCCC2)C[C@H]2[C@@H]3CC[C@H]4C[C@@H](C)C(=O)C[C@]4(C)[C@H]3CC[C@]12C
Reactant: C1CCNCC1
Solvent: O=CO
Product: C[C@@H]1C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)[C@@H](N5CCCCC5)C[C@@H]34)[C@@]2(C)C[C@@H]1N1CCCCC1

Procedure:
17β-Acetyloxy-3β-methyl-16-(1-piperidinyl)-5α-androstan-2-one was treated with piperidine and formic acid, as described in Example I(h), to give 3β-methyl-2β,16β-di-(1-piperidinyl)-5α-androstan-17β-ol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:33][C:25]1[C:26]([C:30]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[O:31])=[C:27]([CH3:29])[NH:28][C:24]=1/[CH:23]=[C:16]1\[C:17](=[O:22])[NH:18][C:19]2[C:15]\1=[CH:14][C:13]([S:10]([CH2:9][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:8])(=[O:11])=[O:12])=[CH:21][CH:20]=2
Reactant: CN1CCNCC1
Reactant: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)O)c1C)C(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)N3CCN(C)CC3)c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[5-(2,6-dimethyl-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.26 mmol), 1-methyl-piperazine (1.2 eq.), HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) in DMF (0.2 M) was stirred at rt for overnight. The reaction was concentrated, diluted with DCM, washed with water, dried and concentrated. The residue was triturated with ethyl ether to give the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>C(OCC)(=O)C.CCCCCC>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH:5]1[C:4]2[C:9](=[N:10][CH:11]=[C:2]([C:29]3[CH:28]=[CH:27][C:26]([N:23]4[CH2:22][CH2:21][O:20][CH2:25][CH2:24]4)=[CH:31][CH:30]=3)[CH:3]=2)[NH:8][CH2:7][CH2:6]1
Reactant: Clc1cccc(OC2CCNc3ncc(Br)cc32)c1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Clc1cccc(OC2CCNc3ncc(-c4ccc(N5CCOCC5)cc4)cc32)c1
Yield: 73 %

Procedure:
6-Bromo-4-(3-chlorophenoxy)-1,2,3,4-tetrahydro-[1,8]naphthyridine (20 mg) was reacted with 4-morpholinophenylboronic acid (20.7 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-100% ethyl acetate/hexane as the eluting solvent gave the title compound as a yellow solid (73% yield). M.p. 124-126° C., LCMS: m/z=422.28 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.0-2.11 (m, 1H), 2.22-2.5 (m, 1H), 3.17 (t, J=4.7 Hz, 4H), 3.38-3.48 (m, 1H), 3.54-3.67 (m, 1H), 3.87 (t, J=4.7 Hz, 4H), 5.10 (s, 1H), 5.37 (t, J=1.0 Hz, 1H), 6.88-7.02 (m, 4H), 7.03-7.07 (m, 1H), 7.21-7.26 (m, 1H), 7.37 (d, J=8.6 Hz, 2H), 7.56 (d, J=1.9 Hz, 1H), 8.25 (d, J=1.9 Hz, 1H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14]=[CH:15][CH:16]([OH:21])[CH2:17][C:18](=[O:20])[CH3:19].N1C=CC=CC=1>CCOCC>[Br:1][CH2:2][C:3]([O:21][CH:16]([CH:15]=[CH:14][C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[Cl:6])[CH2:17][C:18](=[O:20])[CH3:19])=[O:4]
Reactant: CC(=O)CC(O)C=Cc1ccc(Cl)cc1Cl
Reactant: O=C(Br)CBr
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)CC(C=Cc1ccc(Cl)cc1Cl)OC(=O)CBr
Temperature: 20 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
2-Bromoacetyl bromide (1.1 ml, 13.2 mmole) was added dropwise to a stirred solution of 6-(2,4-dichlorophenyl)-4-hydroxy-5-hexene-2-one (3.4 g, 13.1 mmole) and pyridine (1.07 ml, 13.2 mmole) in ether (100 ml) at 0° C. The ice bath was removed and the reaction mixture was stirred at 20° C. for 2 hours and then diluted with H2O (100 ml). The organic layer was separated and washed with 1N HCl (100 ml), H2O (2×100 ml) and brine, dried over MgSO4, filtered and evaporated. The residual oil was chromatographed on a 60 mm column with 15 cm of silica gel (230-400 mesh) Elution with methylene chloride-acetone (99:1; v:v; 1.9 L) provided the title compound (2.8 g, 56%); pmr (CDCl3) δ2.2 (3H, s), 2.92 (2H, t), 3.85 (2H, s), 5.9 (H, m), 6.15 (H, m) 6.95-7.5 (4H, m).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].BrC1C=CC=CC=1>CCOCC>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Solvent: Brc1ccccc1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]ccc23)c(F)c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
To a sealed tube equipped with a magnetic stir bar was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 6.5 mmol, 1.0 eq.), 2-Fluoro-4-nitro-phenol (1.5 g, 9.5 mmol, 1.5 eq) and bromobenzene (5 ml). The mixture was stirred at 130° C. for 4 hours. The reaction mixture was then cooled to room temperature and ether was added (5 ml). After addition of ether the resulting precipitate was filtered and washed with ether. The product was recrystallized from methanol to give 4-(2-fluoro-4-nitro-phenoxy)-7H-pyrrolo[2,3-d]pyrimidine as an off white solid. (1.6 g, 89% yield). 1H NMR (400 MHz, DMSO): 12.44 (s, 1H), 8.41(dd, 1H), 8.34 (s, 1H), 8.24 (m, 1H), 7.80 (m, 1H), 7.61 (m, 1H), 6.69 (d, 1H); MS (ESI) for C12H7FN4O3: 275 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C([O-])(O)=O.[Na+]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH2:7])=[CH:11][CH:12]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
Entire reaction was performed under argon atmosphere using syringe septa technique. ({2-[4-(4-fluoro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (3.018 mmol, 1 eq) was dissolved in dichloromethane (10 ml) and stirred at 0° C. for 5 min. TFA (15.088 mmol, 5 eq) was added and stirring was continued for overnight. Reaction mixture was diluted with 50 ml NaHCO3 (sat.) and extraction with DCM (3×20 ml) followed. Organic layers were combined and evaporated in vacuo to give 2-[4-(4-fluoro-phenoxy)-phenyl]ethylamine (3.027 mmol, yield=94%, purity=94%). [M+H]+=265.25 1H NMR (300 MHz, CDCl3) δ/ppm 2.86 (s, 2H), 3.09 (s, 2H), 7.01 (d, J=8.7 Hz, 5H), 7.24 (s, 2H), 7.37 (s, 1H)
Reaction SMILES: Br[CH2:2][C:3]1([CH3:28])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][N:21]3[CH:25]=[N:24][N:23]=[N:22]3)[C@H:5]2[S:4]1.[CH3:29][N:30]1[C:34]([SH:35])=[N:33][N:32]=[N:31]1>P([O-])([O-])([O-])=O.CC(C)=O>[Cl:13][C:12]([Cl:15])([Cl:14])[CH2:11][O:10][C:8]([CH:7]1[N:6]2[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][N:21]3[CH:25]=[N:24][N:23]=[N:22]3)[C@H:5]2[S:4][C:3]1([CH2:2][S:35][C:34]1[N:30]([CH3:29])[N:31]=[N:32][N:33]=1)[CH3:28])=[O:9]
Reactant: Cn1nnnc1S
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cn3cnnn3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: Cn1nnnc1SCC1(C)S[C@@H]2C(NC(=O)Cn3cnnn3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl

Procedure:
By treating in the similar manner as described in Example 11 using 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl)-acetamido]penam-3-carboxylate and 1-methyl-IH-tetrazole-5-thiol in a mixture of pH 6.85 phosphate buffer and acetone, there was obtained amorphous 2,2,2-trichloroethyl-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl)acetamido]penam-3-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[CH3:2].N1C(C)=CC=CC=1C.Cl[CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[NH:16][CH:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:2]
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCNC(=O)c1cc(I)ccc1N
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1cc(I)ccc1NC(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 56.2 %

Procedure:
A magnetically stirred solution of 1.1 gram of N-(2-amino-5-iodobenzoyl)-b-alanine ethyl ester (3.1 mmol), prepared by the method shown in part (b) of Example 1, 0.48 mL of 2,6-lutidine (4.1 mmol), 1.2 grams of chlorodiphenylmethane (4.7 mmol), and 10 mL of dimethylformamide was heated to 50° C. for 1 hour The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting oil was dissolved in 35 mL of methylene chloride and washed with 2×50 mL 10% citric acid, 1×50 mL water, dried over sodium sulfate, decanted and concentrated in vacuo. The resulting oil was further purified by column chromatography, using silica gel, eluting with a solvent gradient of 10/90 ethyl acetate/hexane to 25/75 ethyl acetate/hexane (TLC, SiO2, 1:1 EtOAc/hexane, Rf =0.82, uv positive) to yield 0.92 gram (56%) of N-(2-diphenylmethylamino-5-iodobenzoyl)-b-alanine ethyl ester. 1H NMR (CDCl3, dTMS) 8.40 (1H, d, 3JHH =5 Hz, NHCHAr2), 7.56 (1H, d, 3JHH =2 Hz, ArH o-CON), 7.18-7.36 (11H, m; 4JHH =2 Hz, ArH Ph, ArH p-CON), 6.73 (1H, t, 3JHH =6 Hz, NHCH2), 6.29 (1H, d, 3JHH =9 Hz, ArH m-CON), 5.52 (1H, d, 3HH=5 Hz, CHNH), 4.15 (2H, q, 3JHH =7 Hz, OCH2), 3.61 (2H, q, 3JHH =6 Hz, CH2NH), 2.58 (2H, t, 3JHH =6 Hz, CH2CO), 1.25 (3H, t, 3JHH =6 Hz, CH3CH2O).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])O.[CH2:7]([OH:9])C.[CH2:10](S(O)(=O)=O)CC[CH2:13][CH2:14][CH3:15]>C(Cl)Cl>[CH3:7][O:9][C:5](=[O:6])[C:3]([CH3:10])=[CH2:2].[C:7]([OH:9])(=[O:1])[C:14]([CH3:13])=[CH2:15]
Reactant: CCO
Reactant: OCC(O)CO
Reactant: CCCCCCS(=O)(=O)O
Solvent: ClCCl
Product: C=C(C)C(=O)O
Product: C=C(C)C(=O)OC

Procedure:
Glycerine, ethyl alcohol and methylene chloride were purchased from Frutarom; enzymatically hydrolyzed gelatin with average molecular weight of 10,000-12,000 was purchased from Croda; hexanesulfonic acid was purchased from BDH; methylmethacrylate-methacrylic acid copolymers were provided from Rhom Pharma; 1-PLA with Mw of 427,000 and Mn of 224,500 was purchased from Boehringer Ingelheim; triethyl citrate was provided by Morflex; ethylcellulose was provided by Teva; polyvinyl pyrrolidone was provided by Taro; glutaraldehyde 25% and acetonitrile were purchased from Merck; chloroform, orthophosphoric acid and trichloroacetic acid were purchased from Baker. All solvents were of analytical grade, except acetonitrile which was HPLC grade.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[CH3:9][O:10][C:11](=[O:23])[CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2.BrCCBr>C1COCC1>[CH3:9][O:10][C:11]([C:12]1([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[CH2:3][CH2:2]1)=[O:23]
Reactant: COC(=O)Cc1ccc2ncccc2c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COC(=O)C1(c2ccc3ncccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
A solution of LDA (1.8 M solution in toluene, 14.8 ml, 26.6 mmol) was added dropwise to a solution of quinolin-6-yl-acetic acid methyl ester (2.14 g, 10.64 mmol) in dry THF (40 mL) under a nitrogen atmosphere at −78° C. After 30 min, 1,2-dibromoethane (2.40 g, 12.76 mmol) was added dropwise over 3 min. The resulting mixture was stirred for 1 h at room temperature, then quenched with satd aq. NH4Cl. The mixture was extracted with DCM, washed with brine, dried over Na2SO4, and stripped of solvent. The residue was purified by flash chromatography in silica gel eluting with a EtOAC/hexane gradient to afford 463 mg (20%) of the title compound as yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.91 (dd, 1H), 8.12 (d, 1H), 8.07 (d, 1H), 7.77-7.74 (m, 2H), 7.40 (dd, 1H), 3.65 (s, 3H), 1.73-1.71 (m, 2H), 1.33-1.30 (m, 2H). LCMS (method A): [MH]+=228, tR=4.37 min.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:7]([OH:18])[C:8]2[C:9]([F:17])=[C:10]([OH:16])[CH:11]=[C:12]([CH2:14][CH3:15])[CH:13]=2)[NH:5][CH:6]=1.[C:19]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([CH:7]([C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:19])[C:9]=2[F:17])[OH:18])[NH:5][CH:6]=1
Reactant: CCc1cc(O)c(F)c(C(O)c2nc(Br)c[nH]2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCc1cc(OC)c(F)c(C(O)c2nc(Br)c[nH]2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 154.4 %

Procedure:
To a solution of Intermediate 206.2 (394 mg, 0.707 mmol) in 5 mL DMF at rt, were added K2CO3 (117 mg, 0.848 mmol) and iodomethane (132 μL, 2.12 mmol). The mixture was stirred at rt for 3 days, then diluted with EtOAc. The organic phase was washed with H2O (2×), sat. Na2SO3, H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 60% EtOAc/hexanes gradient) to afford 359.4 mg of Intermediate 206.3 as a colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].C1C(=O)N([Br:16])C(=O)C1.O>CN(C=O)C>[Br:16][C:5]1[S:1][C:2]([CH2:6][C:7]#[N:8])=[CH:3][CH:4]=1
Reactant: N#CCc1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
To a solution of 2-(thiophen-2-yl)acetonitrile (1.23 g, 10 mmol, 1.0 eq) in DMF (10 mL), NBS (1.96 g, 11 mmol, 1.1 eq) was added. The mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture. After extraction with EtOAc (3×), the organic layers were washed with water, brine, dried (Na2SO4) and filtered. The filtrate was concentrated and the resulting residue was purified by silica gel chromatography (petroleum/EtOAc from 100:1 to 10:1) to affords 2-(5-bromothiophen-2-yl)acetonitrile (738 mg, 60%). LC-MS (m/z)=202 [M+H]+