Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].O1CCOCC1.[C:13](ON1C(=O)CCC1=O)([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14].Cl>O.C(=O)([O-])[O-].[Na+].[Na+]>[C:13]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])([O:15][CH2:16][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: C[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O

Procedure:
1 g of each isotope labeled alanine (11.2 mmol) were dissolved in 15 mL of purified water and 1.2 g of sodium carbonate (see Figure GP2). 15 mL of 1,4-Dioxane was added slowly to each and stirred. Over the period of two and a half hours, 3.8 g of Fmoc-OSu (9-Fluorenylmethyl-N-hydroxysuccinimide) was added to each (see Figure GP3 for scheme). Additional saturated sodium carbonate in water was added to maintain a pH=10. Solutions were allowed to stir overnight. 6M HCl was slowly added to the solution until the pH was approximately 2. Extraction of the compound was completed using two times 150 mL of ethyl acetate, washing four times with 300 mL of acidified/purified water. Magnesium sulfate was added to remove any excess water. Samples were filtered and concentrated using a RotoVap until the final volume was approximately one-third the original volume. Crystallization was completed using Hexane. Hexane was decanted and compound allowed to dry.
Reaction SMILES: [F:1][CH:2]([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14](/[CH:18]=N/NS(C3C=CC(C)=CC=3)(=O)=O)[CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1.[CH2:32](B(CC)CC)[CH3:33].[OH-].[Na+].O>C1COCC1>[F:31][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:32][CH3:33])[CH:13]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)N/N=C/c2cccc(C#Cc3ccc(OC(F)F)cc3)c2)cc1
Reactant: CCB(CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 88.7 %

Procedure:
A mixture of N′-[(1E)-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)methylene]-4-methylbenzenesulfonohydrazide (0.67 mg, 1.52 mmol) in THF was treated with triethyl borane (1.0 M in THF, 1.52 mL, 1.52 mmol), stirred for 2 minutes, treated with NaOH (2.5 N, 0.61 mL, 1.52 mmol), refluxed for 2 hours, cooled to room temperature, poured into water and extracted with EtOAc. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. The resultant residue was purified on silica gel (ISCO) using hexanes/EtOAc (50/1) as the eluting solvents to give 1-{[4-(difluoromethoxy)phenyl]ethynyl}-3-propylbenzene as a clear oil (386 mg, 89% yield), MS m/e (M+H)+ 286; 1H NMR (400 MHz, DMSO-d6) 0.85 (t, J=7.32 Hz, 3H), 1.57 (m, 2H), 2.6 (t, J=7.32 Hz, 2H), 7.2 (m, 3H), 7.35-7.45 (m, 4H), 7.58 (d, J=8.79 Hz, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:16]C)=[N:5][C:6]([CH3:15])=[C:7]([C:9]2[N:13]=[C:12]([CH3:14])[O:11][N:10]=2)[CH:8]=1)[CH3:2].[I-].[Na+].C(#N)C.Cl[Si](C)(C)C>O.CCOCC>[CH2:1]([C:3]1[C:4](=[O:16])[NH:5][C:6]([CH3:15])=[C:7]([C:9]2[N:13]=[C:12]([CH3:14])[O:11][N:10]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-c2noc(C)n2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: CCc1cc(-c2noc(C)n2)c(C)[nH]c1=O
Temperature: 65 °C
Reaction time: 15 h
Yield: 56.5 %

Procedure:
To a mixture of 3-ethyl-2-methoxy-6-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)-pyridine (47 mg, 0.202 mmol) and sodium iodide (91 mg, 0.607 mmol) under a nitrogen atmosphere is added anhydrous acetonitrile (4 mL) followed by drop-wise addition of chlorotrimethylsilane (76 μL, 0.605 mmol). The reaction mixture is stirred at 65° C. under nitrogen for 15 hr. The reaction mixture is allowed to cool, diluted with water and the resulting mixture is extracted with four portions of dichloromethane. The combined extracts are dried over magnesium sulfate and evaporated to leave an orange residue. The crude product is purified by flash chromatography on a 2-gram silica gel cartridge by elution with heptane:dichloromethane: (1:1). Fractions containing the product are combined, the solvent evaporated and the residue triturated with ether to 3-ethyl-6-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-pyridin-2-one (25 mg, 58% yield) as a light yellow powder. LC/MS: RT: 2.39 min, MS: m/e=220 (M+H); 1H NMR (CDCl3, δ, ppm): 12.14 (1H, s), 7.89 (1H, s), 2.70 (3H, s), 2.64 (3H, s), 2.61 (2H, q), 1.24 (3H, t).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([BH3-])#N.[Na+].[CH:22](=O)[CH2:23][CH3:24]>CO>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:22][CH2:23][CH3:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCNCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In methanol (6.0 ml), (4-amino-butyl)-carbamic acid t-butyl ester (400.0 mg) was dissolved. After acetic acid (0.12 ml) and sodium cyanoborohydride (172.5 mg) were added to the solution, propionaldehyde (0.155 ml) was dropped thereto and the whole was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off and the residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (339.6 mg) as a colorless oily substance.
Reaction SMILES: F[C:2]1[C:11]([CH:12]=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[OH:14][CH2:15][CH2:16][NH:17][NH2:18]>CO>[OH:14][CH2:15][CH2:16][N:17]1[C:2]2[C:11](=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:12]=[N:18]1
Reactant: COC(=O)c1cccc(C=O)c1F
Reactant: NNCCO
Solvent: CO
Product: COC(=O)c1cccc2cnn(CCO)c12
Yield: 64.6 %

Procedure:
A mixture of methyl 2-fluoro-3-formylbenzoate (3.6 g, 19.9 mmol) from Step C above and hydroxy ethyl hydrazine (1.5 g, 19.9 mmol) in MeOH (16 mL) was irradiated with microwaves at 150° C. for 1.5 h. The reaction mixture was cooled and partitioned between H2O and ethyl acetate. The aqueous phase was extracted with additional ethyl acetate and then the combined organic extracts were dried (Na2SO4) filtered, concentrated and purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to afford methyl 1-(2-hydroxyethyl)-1H-indazole-7-carboxylate as a yellow solid (2.83 g, 65%): 1H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.18 (t, J=8.5 Hz, 1H), 4.84 (t, J=5.0 Hz, 2H), 4.13-4.07 (m, 2H), 3.99 (s, 3H), 3.20-3.10 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[C:23](Cl)(=[O:29])[CH2:24][CH2:25][C:26](Cl)=[O:27]>CN(C)C=O.CN(C1C=CN=CC=1)C.O>[Cl:16][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[CH:5]=[C:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=[C:2]([N:1]3[C:26](=[O:27])[CH2:25][CH2:24][C:23]3=[O:29])[N:7]=2)[CH:14]=[CH:13][C:12]=1[OH:15]
Reactant: O=C(Cl)CCC(=O)Cl
Reactant: Nc1nc(Nc2ccc(O)c(Cl)c2)cc(-c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC(=O)N1c1nc(Nc2ccc(O)c(Cl)c2)cc(-c2ccccc2)n1

Procedure:
To a solution of compound 4-(2-amino-6-phenyl-pyrimidin-4-ylamino)-2-chloro-phenol (0.5 g, 1.6 mmol) in dry dimethylformamide (10 mL) was added 4-(N,N-dimethylamino)pyridine (0.39 g, 3.2 mmol) at 0° C. with stirring under nitrogen atmosphere. To this was added freshly prepared succinyl chloride (0.62 g, 4 mmol). The mixture was then stirred at 80° C. for 20 hours. After completion of the reaction the mixture was diluted with water (75 mL), the solid separated was filtered off, washed with cold water (200 mL) and dried. The solid was purified further by column chromatography using petroleum ether-ethyl acetate to give the desired product as a light brown solid.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH2:12][CH3:13])=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[I-:14].[K+].II.[N+]([O-])(OC(C)(C)C)=O>C(#N)C.[Cu](I)I>[I:14][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][CH3:13])=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: CCc1ccc(N)c2c1CNC2=O
Reactant: [I-]
Agent: I[Cu]I
Agent: CC(C)(C)O[N+](=O)[O-]
Agent: II
Solvent: CC#N
Product: CCc1ccc(I)c2c1CNC2=O
Yield: 49.7 %

Procedure:
In a similar manner to Step 4 of Example 140, 7-amino-4-ethylisoindolinone (46.0 mg, 0.260 mmol) was dissolved in acetonitrile (6.2 mL), and the solution was treated with potassium iodide (69.1 mg, 0.416 mmol), copper iodide (79.2 mg, 0.416 mmol), iodine (106 mg, 0.416 mmol) and tert-butyl nitrate (0.139 mL, 1.17 mmol), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=5/1) to obtain 7-iodo-4-ethylisoindolinone (37.1 mg, yield 50%).
Reaction SMILES: [CH2:1]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=O)[NH2:23])=[CH:18][N:17]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)(Cl)(Cl)Cl>[CH2:1]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][N:17]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1Cc2ccc(-c3ccc(C(N)=O)cn3)cc2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCC1Cc2ccc(-c3ccc(C#N)cn3)cc2C1
Reaction time: 10 h
Yield: 36.5 %

Procedure:
Then, 2.00 g (6.20 mM) of 2-hexyl-5-(5-carbamoylpyridine-2-yl)indan was dissolved in 20 ml of dry THF. To the solution, a solution of 4.89 g (18.6 mM) of triphenylphosphine in 15 ml of carbon tetrachloride was added, followed by stirring 10 hours to obtain an insoluble matter. The insoluble matter was recovered by filtration and washed with toluene. The resultant mixture was added to the filtrate and evaporated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene/hexane=100/1), followed by distilling-off of the solvent and addition of methanol to obtain an insoluble matter. The insoluble matter was recovered by filtration to obtain 0.69 g of 2-hexyl-5-(5-cyanopyridine-2-yl)indan (Yield: 36.5%). ##STR303## (2) Production of 2-hexyl-5-(5-decanoylpyridine-2-yl)indan
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[C:11]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][N:10]2[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:7]=[CH:6][CH:5]=3)[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[C:11]2[CH:12]=1
Reactant: Nc1cccc(-c2nn3ccc(CO)cc3c2-c2ccncn2)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2nn3ccc(CO)cc3c2-c2ccncn2)c1)c1ccccc1
Reaction time: 8 h

Procedure:
To a suspension of [2-(3-aminophenyl)-3-(4-pyrimidinyl)pyrazolo[1,5-a]pyridin-5-yl]methanol (600 mg, 1.90 mmol) in DCM (60 mL), benzoyl chloride (0.440 mL, 3.79 mmol) was added dropwise at rt. The mixture was stirred for overnight. The reaction mixture was quenched to add MeOH, then the solvent was evaporated under reduced pressure. The residue was recrystallized from DCM (excess) and small amount of acetone. The title compound was obtained as yellow solid (820 mg).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[NH:8][C:7]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:14])[C:6]=2[N:5]=1)[CH3:3].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]Br.C1(C)C=CC=CC=1.[NH4+].[Cl-]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:19][N:5]2[C:6]3[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][C:7]=3[N:8]=[C:4]2[CH:2]([CH3:1])[CH3:3])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: CC(C)c1nc2c([nH]1)CCCCC2=O
Reactant: Clc1ccc(CBr)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(=O)CCCC2
Temperature: 30 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
Tetrabutylammonium bromide (419 mg) was added to a stirred mixture of Intermediate 2 (500 mg, 2.60 mmol) and 3,4-dichlorobenzylbromide (624 mg) in sodium hydroxide 20% aq (3.50 mL) and Toluene (9 mL). The RM was stirred at 30° C. under nitrogen atm for 3 hours. An excess of sat NH4Cl aq solution was added and the mixture was extracted with EtOAc (3×30 ml). The organics were combined, dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (630 mg). LC/MS MH+ 351/353, Rt 3.16 min (5 minute run).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:14])=[C:6](B(O)O)[C:7]([F:10])=[CH:8][CH:9]=1)[CH3:2].C(O)(=[O:17])C.OO>O1CCCC1>[CH2:1]([O:3][C:4]1[C:5]([F:14])=[C:6]([OH:17])[C:7]([F:10])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(B(O)O)c1F
Reactant: CC(=O)O
Agent: OO
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(O)c1F
Reaction time: 65 h
Yield: 99 %

Procedure:
To a solution of 3-ethoxy-2,6-difluoro-phenylboronic acid (5.0 g, 0.025 mol) in tetrahydrofuran (80 mL) was added glacial acetic acid (30 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 4 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 65 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 3-ethoxy-2,6-difluoro-phenol (4.25 g, 99%) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:24]([O-])=O)[C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[NH2:27][C:28]1[N:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O.ClCCl.CO.CS(C)=O>[NH2:27][C:28]1[C:29]([C:30]2[N:8]([C:9]3[CH:23]=[CH:22][C:12]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11][CH:10]=3)[C:5]3=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]3[N:24]=2)=[CH:32][CH:33]=[CH:34][N:35]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2ncc(Br)cc2[N+](=O)[O-])cc1
Reactant: Nc1ncccc1C=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(-n2c(-c3cccnc3N)nc3cc(Br)cnc32)cc1
Temperature: 100 °C
Reaction time: 36 h
Yield: 40.4 %

Procedure:
tert-butyl 4-((5-bromo-3-nitropyridin-2-yl)amino)benzylcarbamate (25.0 g, 58.9 mmol), 2-aminonicotinaldehyde (10.2 g, 83.5 mmol), sodium dithionite (31.0 g, 178 mmol), methanol (80 mL), and DMSO (500 mL) were placed in a round-bottomed flask which was allowed to stir at 100° C. for 36 h. After cooling to room temperature the mixture was diluted with ethyl acetate (500 mL) and water (500 mL). The layers were separated, the organic layer was washed with water (2×300 mL) and concentrated to yield the crude product as a black oily solid (29.2 g). Column chromatography (1-5% methanol in dichloromethane) yielded an orange solid which could be further purified by re-crystallization (ethyl acetate/hexanes, 1:1) to yield tert-butyl 4-(2-(2-aminopyridin-3-yl)-6-bromo-3H-imidazo[4,5-b]pyridine-3-yl)benzylcarbamate (11.8 g, 23.8 mmol, 41%) as an off-white solid. Mp. 176-178° C.; 400 M Hz 1H NMR (DMSO-d6) δ: 8.50 (d, J=2.0 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H), 7.99 (dd, J=2.0 Hz and 4.7 Hz, 1H), 7.48 (t, J=5.6 Hz, 1H), 7.40-7.31 (m, 3H), 7.23 (dd, J=2.0 Hz and 7.8 Hz, 1H), 6.97 (s, 2H), 6.40 (dd, J=4.4 Hz and 7.7 Hz, 1H), 4.121 (d, J=6.2 Hz, 2H), 1.41 (s, 9H), MS 495.34, 497.23 [M+H, M+2+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:20])[CH2:16][C:17](=O)[CH3:18])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:21]([C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[O:26][CH2:27][C:28]([NH2:30])=O)#[CH:22].C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1(C)C(C)=CC=CC=1.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]2[C:15](=[O:20])[CH:16]=[C:17]([CH3:18])[N:30]=[C:28]2[CH2:27][O:26][C:25]2[CH:31]=[CH:32][CH:33]=[C:23]([C:21]#[CH:22])[CH:24]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: C#Cc1cccc(OCC(N)=O)c1
Reactant: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(Cl)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: C#Cc1cccc(OCc2nc(C)cc(=O)n2-c2ccc(N3CCOCC3)c(Cl)c2)c1
Temperature: 165 °C
Reaction time: 24 h
Yield: 48.3 %

Procedure:
A mixture of N-(3-chloro-4-morpholinophenyl)-3-oxobutanamide (0.80 g, 2.85 mmol), 2-(3-ethynylphenoxy)acetamide (1.0 g, 5.71 mmol) and titanium tetraisopropanolate (6.76 mL) in xylene (20 mL) was stirred at 165° C. for 24 h. The mixture was cooled to rt and 50 mL of toluene and 60 mL of saturated NH4Cl aqueous solution were added. The resulting mixture was stirred at rt overnight and filtered and the filtrate was extracted with DCM (150 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (0.60 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[C:8]([C:10](=O)[CH2:11][NH2:12])[CH:7]=[CH:6][N:5]=1.[S-:14][C:15]#[N:16].[K+]>O>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[NH:16][C:15](=[S:14])[NH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: N#C[S-]
Reactant: Cc1cc(C(=O)CN)ccn1
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1cc(-c2c[nH]c(=S)[nH]2)ccn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a stirred solution of crude 1-(2-methyl-pyridin-4-yl)-2-amino-ethanone dihydrochloride (8.50 g, 35.8 mmol) in water (60 ml) was added at room temperature potassium thiocyanate (16.4 g, 168 mmol) and the reaction mixture was heated under reflux conditions for 3 h and at 0° C. for 2 h. The precipitated solid was collected by filtration, saturated sodium bicarbonate solution (100 ml) was added and the mixture was stirred at room temperature for 2 h. The product was collected by filtration to give 4-(2-methylpyridin-4-yl)-1,3-dihydro-imidazole-2-thione (5.44 g, 79%) as a light brown solid; MS (ISP) 192.2 [(M+H)+].
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.C(Cl)[Cl:25].[ClH:27]>O1CCOCC1>[ClH:25].[ClH:27].[ClH:25].[CH3:22][CH:19]1[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)[CH2:21][CH2:20]1
Reactant: CC1CCN(CCN2CCC(NC(=O)OC(C)(C)C)CC2)CC1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: CC1CCN(CCN2CCC(N)CC2)CC1

Procedure:
The tert-butyl ester 9 (2 g, 6.14 mmol) is suspended in 10 ml of dioxane. DCM is then added until the solid dissolved. To this mixture, 4M-HCl in dioxane (12.3 ml, 49.2 mmol) is added. After stirring over night the solvents are evaporated to leave a white solid product.
Reaction SMILES: [Mg].[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:3].[Cl:12][Si:13](Cl)([CH3:15])[CH3:14]>O1CCCC1>[Cl:12][Si:13]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:2][CH3:3])=[CH:6][CH:7]=1)([CH3:15])[CH3:14]
Reactant: C[Si](C)(Cl)Cl
Reactant: CCOc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc([Si](C)(C)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 3.5 g (0.14 mole) of magnesium powder in 100 ml of dry tetrahydrofuran was added dropwise 17.5 g (0.14 mole) of p-bromophenyl ethyl ether during a one hour period. The mixture was warmed for one hour and then cooled to room temperature. The reaction mixture was added dropwise to a solution of dichlorodimethylsilane in 100 ml of dry tetrahydrofuran which was cooled to -78° C. Upon completion of addition the reaction mixture was allowed to warm to room temperature. Stirring was continued overnight. After dilution with hexane, the reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure, leaving a liquid residue. Distillation of this residue yielded 18 g of chloro(4-ethoxyphenyl)dimethylsilane as a clear, colorless oil, b.p. 79°-81° C./0.09 mm of Hg.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][SH:9].[CH3:10][O:11][C:12](=[O:44])[C:13](=[N:32]OS(C1C=CC(C)=CC=1)(=O)=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:28][N:29]=[CH:30][CH3:31])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[CH3:10][O:11][C:12](=[O:44])[C:13](=[N:32][S:9][CH3:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:28][N:29]=[CH:30][CH3:31])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1
Reactant: CC=NOC(c1ccc(Cl)cc1)c1ccccc1C(=NOS(=O)(=O)c1ccc(C)cc1)C(=O)OC
Reactant: CS
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC=NOC(c1ccc(Cl)cc1)c1ccccc1C(=NSC)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2 ml triethylamine in 15 ml chloroform saturated with methanethiol are added 5.15 g (10 mmol) 2-{2-[1-(4-chloro-phenyl)-ethylideneaminooxymethyl]-phenyl}-tosyloxyimino-acetic acid methyl ester. The mixture was stirred at room temperature for 48 hours. After evaporation the residue is purified by silicagel chromatography (ethyl acetate 1, hexanes 5) to give—after elution of 2-[1-(4-chloro-phenyl)-ethylideneaminooxymethyl]-benzonitrile as by-product—1.0 g (28%) of the 2-{2-[1-(4-chloro-phenyl)-ethylideneamino-oxymethyl]-phenyl}-methylthioimino-acetic acid methyl ester. Melting point of 112-113° C.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].[N:10]1[C:17]([Cl:18])=[N:16][C:14](Cl)=[N:13][C:11]=1[Cl:12].C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:12][C:11]1[N:10]=[C:17]([Cl:18])[N:16]=[C:14]([NH:2][N:3]2[CH2:9][C:7](=[O:8])[NH:6][C:4]2=[O:5])[N:13]=1
Reactant: NN1CC(=O)NC1=O
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C1CN(Nc2nc(Cl)nc(Cl)n2)C(=O)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 107.2 %

Procedure:
An ice-cold suspension of 1-aminohydantoin hydrochloride (457 mg, 3.0 mmol), cyanuric chloride (500 mg, 2.73 mmol) and sodium bicarbonate (505 mg, 6 mmol) in acetonitrile (5 mL) was stirred under an atmosphere of nitrogen for 2 h and then stirred at room temperature for 20 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue was extracted with ethyl acetate and the ethyl acetate was separated and dried (MgSO4). The crude product (770 mg) gave a single spot on thin layer chromatography [silica; CH2Cl2/MeOH (10:1)] and was used in the next step without further purification. NMR (CD3CN): δ=4.11 (s, 2H); 8.71 (s, 1H); 8.85 (s, 1H).