Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32][C:33]1[C:42]([OH:43])=[CH:41][CH:40]=[C:39]2[C:34]=1[CH:35]=[CH:36][N:37]=[CH:38]2.[C:44]([O:48][C:49](=[O:58])[NH:50][C@H:51]1[CH2:56][CH2:55][C@H:54](O)[CH2:53][CH2:52]1)([CH3:47])([CH3:46])[CH3:45].C(N(CC)CC)C>ClCCl>[C:44]([O:48][C:49](=[O:58])[NH:50][C@H:51]1[CH2:52][CH2:53][C@@H:54]([O:43][C:42]2[C:33]([Br:32])=[C:34]3[C:39](=[CH:40][CH:41]=2)[CH:38]=[N:37][CH:36]=[CH:35]3)[CH2:55][CH2:56]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: Oc1ccc2cnccc2c1Br
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2ccc3cnccc3c2Br)CC1
Reaction time: 0.25 h
Yield: 23.9 %

Procedure:
4.33 mL (5.75 g, 33 mmol) of diethyl azo dicarboxylate were added to 18 g (68.75 mmol) of triphenylphosphine in 500 mL of dichloromethane at 0° C. and stirred for 15 min. 6.16 g (27.5 mmol) 5-bromo-isoquinolin-6-ol (2), 5.92 g (27.5 mmol) (trans-4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester and 3.81 mL (33 mmol) triethyl amine were added. The mixture was stirred for 4 days. The precipitate was removed by filtration, washed with dichloromethane and the solvents were distilled off. The crude product was purified by flash chromatography using ethyl acetate/n-heptane as eluent to give 2.77 g (24%) of 85. Rt=1.37 min (Method #1). Detected mass: 421.1/423.1 (M+H+).
Reaction SMILES: [I:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13]([O:18][CH2:19][CH2:20]O)(=[O:17])[C:14]([CH3:16])=[CH2:15].C1(N=C=NC2CCCCC2)CCCCC1>CCOCC>[C:13]([O:18][CH2:19][CH2:20][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([I:12])[CH:9]=[C:10]([I:11])[C:2]=1[I:1])(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: O=C(O)c1cc(I)cc(I)c1I
Reactant: C=C(C)C(=O)OCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: C=C(C)C(=O)OCCOC(=O)c1cc(I)cc(I)c1I

Procedure:
2,3,5-triiodobenzoic acid (25 g), 2-hydroxyethyl methacrylate (7.2 g), 1,3-dicyclohexylcarbodiimide (11.5 g) and 4-pyrrilidinopyridine (0.75 g) were stirred in ether suspension (250 ml) at room temperature for 24 hr. The solid was filtered off and the residue washed with fresh ether. The ether solution was extracted with dilute HCl (0.2M) and then with saturated sodium bicarbonate solution. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The residue (21.1 g) was recrystallised from ethyl acetate to give a pure material as white crystals m.pt.94° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>C(#N)C.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.[Cu]I>[OH:29][CH2:25][CH2:26][C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: Cc1ccn2cc(-c3ccc(Br)cc3)nc2c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccn2cc(-c3ccc(C#CCCO)cc3)nc2c1
Temperature: 60 °C
Yield: 71.7 %

Procedure:
The product of Step A (1.8 g) in dry acetonitrile (40 mL) was treated sequentially with tetrakis(triphenylphosphine)palladium(0) (0.1 g), triethylamine (1.27 g), and CuI (10 mg) then heated at 60° C. for 30 minutes. The mixture was cooled to ambient temperature, treated with 3-butyn-1-ol (0.361 g) and heated at reflux temperature for 18 hours. The mixture was cooled to ambient temperature and evaporated to dryness. The residue was crystallized, twice, from acetone to afford the title compound (1.02 g).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>O1CCOCC1.O>[F:27][C:12]([F:11])([F:26])[C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:2]2[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=2)[CH2:18][CH2:17]1
Reactant: COC(=O)c1cnc(Br)s1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Temperature: 82.5 °C

Procedure:
A mixture of methyl 2-bromo-1,3-thiazole-5-carboxylate (10 g, 45 mmol) and 4-[2-(trifluoromethyl)phenoxy]piperidine (12.1 g, 50 mmol) in dioxane (160 mL) was heated at 80-85° C. overnight. After cooling, the mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed twice with water, dried (Na2SO4) and concentrated. The crude material was purified by column chromatography on silica gel (eluting with 50% EtOAc/hexanes) to afford the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22]CC)=[O:21].[OH-].[Na+].Cl>CCO.O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC3CCCCC3)c2c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc2cccc(OC3CCCCC3)c2c(N)c1C(=O)O
Temperature: 0 °C
Yield: 99.4 %

Procedure:
To a solution of ethyl 4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate (Example 36a, 110 g, 0.335 mol) in EtOH (450 mL) was added a solution of NaOH (33.5 g, 0.837 mol) in water (200 mL) at room temperature. The reaction mixture was then refluxed overnight. The reaction solution was cooled down to 0° C. and carefully neutralized with 4N HCl to pH 7. The resultant solution was concentrated under reduced pressure to remove most of the EtOH. The precipitate was collected by filtration, and re-dissolved in EtOH (4 L) at 65° C. and treated with activated charcoal (5 g) for 0.5 h. The charcoal was removed by filtration over celite, and the filtrate was concentrated. The precipitate was collected by filtration, washed with cold water, and dried under vacuum at 60° C. overnight to give the title compound as a white solid (100 g, 99%). M.p.: 220.0-221.5° C. 1H NMR (400 MHz, DMSO-d6) δ 1.28-1.72 (m, 8H), 2.00-2.04 (m, 2H), 2.75 (s, 3H), 4.69-4.71 (m, 1H), 7.10-7.12 (d, J=8.0 Hz, 1H), 7.24-7.26 (d, J=8.0 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 12.80 (brs, 1H). MS 301 (MH+). Elemental Analysis Calculated (Found) for C17H20N2O3: C, 67.98%; (67.74%); H, 6.71%; (7.01%); N, 9.33%; (9.40%).
Reaction SMILES: O.ON1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2N=N1.C(N(C(C)C)[CH:15]([CH3:17])[CH3:16])C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:16]1[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:17][CH2:15]1
Reactant: CCN(C(C)C)C(C)C
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: c1ccc2c(c1)CCC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-Hydroxybenzotriazole hydrate (0.3 eq.) and N-ethyl-diisopropylamine (4 eq.) were added to a solution of (G) (1.5 eq.) in methylene chloride. The reaction mixture was cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq.) was then added. The mixture was stirred at this temperature for 15 min, before the amine (1 eq.) was finally added. The reaction mixture was then stirred at room temperature overnight. For working up, the reaction mixture was washed 3× with 0.5 M KOH solution and the organic phase was dried over MgSO4, filtered and concentrated. The crude product was either purified by column chromatography (silica; methylene chloride/methanol or aluminium oxide; methylene chloride/methanol) or recrystallized from methylene chloride to obtain the product (H) in a pure form.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:24][N:25]2C(=O)C3C(=CC=CC=3)C2=O)=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:7]=1.O.NN>CCO>[Cl:1][C:2]1[C:3]([CH2:24][NH2:25])=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:12])[F:13])[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ncc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1ncc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Yield: 64.9 %

Procedure:
To a stirred solution of (E)-2-((3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione (200 mg, 0.358 mmol) in EtOH (5 mL) was added hydrazine hydrate (89.6 mg, 1.79 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in CH2Cl2. The organic layer was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (100 mg). The product obtained in this reaction was carried on to the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]([CH3:16])[CH2:3]1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26](O)=[O:27])=[N:18]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:9]([N:7]1[CH2:8][CH:2]([NH:1][C:26]([C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17][N:18]=2)=[O:27])[CH2:3][N:4]([CH3:16])[CH2:5][CH2:6]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN1CCN(Cc2ccccc2)CC(N)C1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN1CCN(Cc2ccccc2)CC(NC(=O)c2n[nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a solution of 6-amino-1-benzyl-4-methyl-hexahydro-1H-1,4-diazepine (1.0 g) in dichloromethane (20 ml), 1H-indazole-3-carboxylic acid (740 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (877 mg) are added, and the resulting mixture is stirred at 25° C. for 2 hours. The reaction mixture is washed successively with water and 10% aqueous sodium hydroxide solution, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution of acetone. Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (0.9 g) as an oil. The free base thus obtained is converted to the hemifumarate of the title compound in a usual manner, m.p. 192-194° C. (recrystallized from ethanol).
Reaction SMILES: I[C:2]1[C:3]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][C:8]([C:3]1[C:2]([C:14]#[C:13][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:7][CH:6]=[CH:5][N:4]=1)([CH3:12])[C:9]#[N:10]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C#N)c1ncccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(C)(C#N)c1ncccc1C#C[Si](C)(C)C
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
2-(3-Iodopyridin-2-yl)-2-methylpropanenitrile (1.8 g, 6.6 mmol), cuprous iodide (0.045 mL, 1.3 mmol) and dichlorobis(triphenylphosphine)palladium (II) (0.46 g, 0.66 mmol) were dissolved in TEA (20 mL, 143 mmol). Ethynyltrimethylsilane (4.7 mL, 33 mmol) was added to the reaction mixture, and the reaction mixture was placed under an argon atmosphere. The reaction mixture was stirred and heated at 80° C. After 45 minutes, the reaction was >95% complete as determined by LCMS. The reaction was cooled to room temperature and then filtered through Celite to remove a dark solid. The filtrate was concentrated in vacuo and purified by silica flash chromatography (0-50% EtOAc/hexane) to give the title compound as a light-orange oil (1.6 g, 100%). MS (m/z)=243 (M+H)+. Calculated for C14H18N2Si 242.4.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:26])[NH:8][C:9]1[S:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[C:10]=1[C:23]([NH2:25])=[O:24].[H][H]>CO.[Pt]=O>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]([C:23]([NH2:25])=[O:24])=[C:9]([NH:8][C:7]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[O:26])[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: COCCCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Agent: O=[Pt]
Solvent: CO
Product: COCCCNC(=O)Nc1snc(-c2ccc(N)cc2)c1C(N)=O
Reaction time: 17 h

Procedure:
A mixture of 5-(3-(3-methoxypropyl)ureido)-3-(4-nitrophenyl)isothiazole-4-carboxamide (4 mg, 0.009 mmol) and catalytic platinum oxide in 4 mL MeOH was hydrogenated under 60 PSI hydrogen. After 17 hours, the mixture was filtered and rotary evaporated to a white solid. The solid was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer dried with anhydrous Na2SO4 and evaporated to the title compound as a white solid (2 mg, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[CH3:32][NH:33][CH2:34][C:35]([OH:37])=[O:36]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH2:28][N:33]([CH3:32])[CH2:34][C:35]([OH:37])=[O:36])=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: CNCC(=O)O
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: CN(CC(=O)O)Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and 2-(methylamino)acetic acid (43.2 mg; 0.48 mmol) to give Example 130 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.76-8.73 (2H, m), 7.97 (2H, d, J=8.0 Hz), 7.93-7.88 (1H, m), 7.76-7.69 (1H, m), 7.63-7.58 (2H, m), 7.61-7.47 (4H, m), 3.78 (2H, s), 3.26 (2H, s), 2.32 (3H, s). LC/MS (Method C): 484 (M+H)+. HPLC (Method E) Rt 2.36 min (Purity: 98.9%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]Br.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OC)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=3)([C:15]([F:17])([F:18])[F:16])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: NCc1ccccn1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CBr)c(Br)c2)=NO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CC#N
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CNCc3ccccn3)c(Br)c2)=NO1
Yield: 52.9 %

Procedure:
A solution of 3-[3-bromo-4-(bromomethyl)phenyl]-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (1.8 g), 2-aminomethylpyridine (0.38 g) and potassium carbonate (0.97 g) in acetonitrile (20 mL) was heated to reflux for 3 hours. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to yield 1-{2-bromo-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]phenyl}-N-(pyridin-2-ylmethyl)methanamine (1.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10](/[CH:13]=[C:14](/[C:17]([O:19]C)=[O:18])\[CH2:15][CH3:16])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Li+]>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[S:9][C:10](/[CH:13]=[C:14](\[CH2:15][CH3:16])/[C:17]([OH:19])=[O:18])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC/C(=C\c1ccc(C(=O)OC(C)(C)C)s1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC/C(=C\c1ccc(C(=O)OC(C)(C)C)s1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
5-[(1E)-2-(Methoxycarbonyl)-but-1-en-1-yl]thiophene-2-carboxylic acid tert-butyl ester (34.6 g, 120 mol) was dissolved in tetrahydrofuran (150 mL), and methanol (60 mL), 1 N lithium hydroxide solution (144 mL, 144 mmol) was added, and the mixture was stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure. 0.5 N-Hydrochloric acid solution and ethyl acetate were added to the obtained residue, the organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent of the filtrate was evaporated under reduced pressure to give the title compound (32.2 g, 114 mmol, 95%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([CH:9]1[C:14](=[O:15])[O:13][C:12]([CH3:17])(C)OC1=O)=[O:8])=[N+:2]=[N-:3].OCC[C:22]#[N:23].C(=O)=O>C(Cl)Cl>[C:22]([CH2:17][CH2:12][O:13][C:14](=[O:15])[CH2:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])#[N:23]
Reactant: N#CCCO
Reactant: CC1(C)OC(=O)C(C(=O)CCCN=[N+]=[N-])C(=O)O1
Agent: O=C=O
Solvent: ClCCl
Product: N#CCCOC(=O)CC(=O)CCCN=[N+]=[N-]

Procedure:
5-(4-Azidobutanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was heated with 3-hydroxypropionitrile (5.25 g, 72.0 mmol) at 80° C. until no more CO2 was released. The reaction mixture was diluted with CH2Cl2 (100 ml), washed with water (100 ml) and brine (100 ml). After drying and evaporation of solvent, the product was purified by chromatography (SiO2, CHCl3:MeOH=95:5), 4-azidobutanoylacetic acid 2-cyanoethyl ester was obtained as a yellowish oil (2.86 g, 53.2%).
Reaction SMILES: [H-].[Na+].[CH:3](=O)[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].Cl[CH2:13][C:14]([NH:16][C:17]1[CH:18]=[N:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=1)=[O:15].C[O-].[Na+]>CN(C)C=O.O>[C:23]([C:20]1[N:19]=[CH:18][C:17]([NH:16][C:14]([C:13]2[O:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[CH:3]=2)=[O:15])=[CH:22][CH:21]=1)#[N:24]
Reactant: N#Cc1ccc(NC(=O)CCl)cn1
Reactant: O=Cc1ccccc1O
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(NC(=O)c2cc3ccccc3o2)cn1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.184 g, 7.6 mmol) in dry dimethyl formamide (20 mL), a solution of salicylaldehyde (0.947 g, 7.6 mmol) in dry dimethylformamide (20 mL) was added dropwise under stirring. Stirring was continued for 30 minutes, and compound of example 3 (1.5 g, 7.6mmol) was added to the reaction mixture and heated at 80° C. for 2 hours. To this reaction mixture was added a solution of sodium methoxide (0.044 g) and stirred for 1 hour at 80° C. The reaction mixture was cooled, diluted with water and extracted with chloroform (3×100 mL). Chloroform layer was dried over sodium sulfate and concentrated. The crude product was purified using repetitive column chromatography (silica gel, ethyl acetate/petroleum ether followed by chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [Na].[CH3:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH3:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH2:11][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1
Reactant: CSc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Product: CCOC(=O)C(=O)CC(=O)c1ccc(SC)cc1

Procedure:
The title compound was prepared in the same manner as for intermediate 66 using sodium metal (0.160 g, 6.95 mmol), 1-[4-(methylthio)phenyl]ethanone (1.05 g, 6.32 mmol) and diethyl ethanedioate (0.856 mL, 6.32 mmol). The product was collected as 1.58 g (59%). LCMS E-S (M+H)=266.9. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29-1.50 (m, 3 H), 2.41-2.62 (m, 3 H), 4.23-4.49 (m, 2 H), 7.15-7.38 (m, 2 H), 7.89 (dd, J=8.72, 2.15 Hz, 2 H).
Reaction SMILES: I[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:3]=1.[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][C:23]#[CH:24])[CH3:20]>>[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][C:23]#[C:24][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:3]=1)[CH3:20]
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)cc1
Reactant: C#CCN(CC)CC
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N)cc3)c2s1

Procedure:
Prepared from 4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 72, Step A; 130 mg, 0.353 mmol), and N,N-diethylprop-2-yn-1-amine (58.9 mg, 0.530 mmol), according to the procedure for Example 6, Step B. The product was purified by Biotage 40S column (EtOAc). Product was an orange oil which crystallized upon standing (40 mg, 31%). 1H NMR (CDCl3, 400 MHz) δ 8.46 (d, J=5.5 Hz, 1H), 7.57 (s, 1H), 6.96 (d, J=9 Hz, 2H), 6.72 (d, J=9 Hz, 2H), 6.52 (d, J=5 Hz, 1H), 3.77 (s, 2H), 3.71 (s, 2H), 2.64 (q, J=7, 14 Hz, 4H), 1.13 (t, J=7 Hz, 6H). LRMS (ESI pos) m/e 352 (M+1).
Reaction SMILES: Cl.C(O[C:5](=[NH:14])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)C.[CH:15]1([NH2:18])[CH2:17][CH2:16]1>C(Cl)Cl>[CH:15]1([NH:18][C:5](=[NH:14])[C:6]2[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)[CH2:17][CH2:16]1
Reactant: CCOC(=N)c1ccc(OC)cc1
Reactant: NC1CC1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=N)NC2CC2)cc1
Reaction time: 3 h
Yield: 81.6 %

Procedure:
4-methoxy-benzimidic acid ethyl ester hydrochloride (1.25 g, 5.8 mmol), DCM (5 ml) and cyclopropylamine (0.92 ml, 13.3 mmol) were mixed. After stirring at r.t for 3 h, the reaction mixture was concentrated in-vacuo. The residue was treated with cold aq. sodium hydroxide (1M) and extracted with EA. The combined organic phase was washed with water and brine, dried (Na2SO4), filtered and concentrated in-vacuo, to isolate the title compound (0.90 g, 82%). 1H-NMR: 7.64 (d, 2H), 6.90 (d, 2H), 5.3 (bs, 2H), 3.85 (s, 3H), 2.59 (m, 1H), 0.84 (m, 2H), 0.62 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[CH:31][CH:32]=2)=[CH:24][CH:25]=1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: c1cscn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(I)cc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(-c3nccs3)cc2)cc1
Yield: 99.9 %

Procedure:
The title compound (90 mg, 99%) was prepared from thiazole (0.07 g, 0.8 mmol) and (R)-2-[4-(4-iodo-benzyl)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.2 mmol) using the procedure of Example 146, step 1, 1HNMR (400 Hz, CDCl3) δ 7.88 (d, J=8.4 Hz, 2H), 7.84 (d, J=3.2 Hz, 1H), 7.30 (d, J=3.2 Hz, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.10 (d, J=8 Hz, 2H), 6.86 (br d, J=7.2 Hz, 2H), 4.10 (br, 2H), 3.96 (s, 2H), 3.9-3.75 (br, 2H), 3.40 (br, 2H), 2.03-1.84 (br, 4H), 1.46 (s, 9H) MS?