Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:47][C@@H:48]([CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[CH2:49][C@H:50]([OH:69])[C@@H:51]([NH:59][C:60]([O:62][CH2:63][C:64]1[S:68][CH:67]=[N:66][CH:65]=1)=[O:61])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([NH:47][C@@H:48]([CH2:70][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)[CH2:49][C@H:50]([OH:69])[C@@H:51]([NH:59][C:60]([O:62][CH2:63][C:64]1[S:68][CH:67]=[N:66][CH:65]=1)=[O:61])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:21])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:10])[CH3:11])[S:7][CH:8]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine (4.13g, 13.18 mmole) and hydroxybenztriazole (2.23 g, 16.48 mmoles) were dissolved in 70 mL THF and then dicyclohexyl-carbodiimide(2.71 g, 13.18 mmoles) was added in one portion to the stirred solution under nitrogen atmosphere. This mixture was stirred for 4h at room temperature and then filtered to remove dicyclohexylurea precipitate. The product of Example 69B (5.1 g, 11.99 mmoles) was dissolved in 100 mL THF under nitrogen atmosphere. To this stirred solution was added the filtrate of HOBT-active ester and the resulting solution was stirred at room temperature for 4 h, and the solvent removed via rotary evaporation. The residue was dissolved in 150 mL ethyl acetate and washed with 2×100 mL 1N NaOH, 100 mL brine, 100 mL of 1% w/w aqueous KHSO4 and the solvent was removed by rotary evaporation to afford a residue. The residue was dissolved in 175 mL 1N HCL, and the solution filtered to remove the small quantity of dicyclohexylurea. The filtrate solution was added to 175 mL ethyl acetate and the two phase mixture rapidly mixed. The pH of this rapidly stirred mixture was adjusted to pH=7 by dropwise addition of cold 3N NaOH. The organic layer was isolated, washed with 100 mL brine, dried over Na2SO4, filtered, and the solvent was removed to afford 8.6 g of a colorless foam. This material was crystallized from 42 mL EtOAc and 21 mL hexane to give 7.85 g of the desired product as a white solid. mp=122°-123° C. CIMS m/z 721 (M+H)+.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[C:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7].CO[C:13]1C=CC(O)=C[CH:14]=1.C(=O)=O>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC>[C:5](=[O:8])([O:6][CH3:7])[O:10][CH2:1][CH:2]=[CH2:3].[C:5](=[O:10])([O:8][CH2:9][CH:13]=[CH2:14])[O:6][CH2:1][CH:2]=[CH2:3]
Reactant: COC(=O)OC
Reactant: COc1ccc(O)cc1
Reactant: C=CCCl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: O=C=O
Agent: [Br-]
Product: C=CCOC(=O)OC
Product: C=CCOC(=O)OCC=C
Temperature: 150 °C
Yield: 3.4 %
Yield: 25 %

Procedure:
The reaction conditions of Example 1 are substantially repeated employing allyl chloride (76.5 g, 1.0 mole), dimethyl carbonate (90.0 g, 1.0 mole), tetra-n--butylphosphonium bromide (6.78 g, 0.02 mole) and p-methoxyphenol (0.5 g, 0.004 mole) polymerization inhibitors. After heating for 7 hours at 150° C. and 600 psi carbon dioxide pressure, the reactor is cooled to room temperature and vented. Distillation gives 29.0 g (25 percent yield) of allyl methyl carbonate having b.p. of 79° C.-80° C. (150 torr) and 4.8 g (3.4 percent yield) of diallyl carbonate having b.p. of 107° C.-108° C. (150 torr).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[S-:11][C:12]#[N:13].[Na+].BrBr.O>C(O)(=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CSc1ccc(N)c([N+](=O)[O-])c1
Temperature: 15 °C
Yield: 91.8 %

Procedure:
A stirred mixture of o-nitroaniline (82.5 g), dry sodium thiocyanate (180 g) and acetic acid (1 liter) was treated at 11°-12° C with a solution of bromine (96.5 g) in acetic acid (100 ml). The stirring was continued for a further hour at 11°-12° C and the mixture was then allowed to warm to 15° C and poured into water (3.5 liters). The yellow solid was filtered off, washed with water, and dissolved in acetone (1 liter). The solution was filtered and the filtrate was evaporated to give 2-nitro-4-thiocyanatoaniline (107 g), m.p. 110°-112° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:14][CH3:15])[CH2:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:16]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].CCOCC>C1COCC1.N1C=CC=CC=1>[CH3:1][CH:2]([CH2:14][CH3:15])[CH2:3][O:4][C:5](=[O:13])[C:6]1[CH:7]=[CH:8][C:9]([O:12][C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([O:26][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:35][CH:34]=2)=[CH:10][CH:11]=1
Reactant: O=C(OCc1ccccc1)Oc1ccc(C(=O)Cl)cc1
Reactant: CCC(C)COC(=O)c1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC(C)COC(=O)c1ccc(OC(=O)c2ccc(OC(=O)OCc3ccccc3)cc2)cc1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of 16 m moles(3.3 g) of the above 4-hydroxybenzoic acid 2-methylbutyl ester in 20 ml of THF and 40 ml of pyridine was cooled, and a THF solution of 10 m moles(2.9 g) of the above 4-carbobenzoxyoxybenzoyl chloride was added dropwise. The mixture was returned slowly to room temperature, then stirred for 8 hours. After the reaction, the reaction mixture was ether extracted and concentrated, and then purified by column chromatography to obtain 2.9 g of 4-(4'-carbobenzoxyoxybenzoyloxy)benzoic acid 2-methylbutyl ester [m.p. 64.4°-65.4° C⟧ (yield: 63%)
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[N:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20].CON(C)[C:24]([C:26]1[CH:34]=[CH:33][C:29]2[O:30][CH2:31][O:32][C:28]=2[CH:27]=1)=[O:25]>C1COCC1>[O:30]1[C:29]2[CH:33]=[CH:34][C:26]([C:24](=[O:25])[CH2:20][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[N:13]=3)=[CH:27][C:28]=2[O:32][CH2:31]1
Reactant: CON(C)C(=O)c1ccc2c(c1)OCO2
Reactant: Cc1cccc(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cccc(CC(=O)c2ccc3c(c2)OCO3)n1
Temperature: 0 °C
Reaction time: 0.1 h
Yield: 87.5 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 13.8 mL, 34.4 mmol) was added slowly to a solution of diisopropylamine (4.53 mL, 32.3 mmol) in anhydrous THF (50 mL) at −78° C. After being stirred for 0.1 hour, the mixture was allowed to warm up to 0° C. Stirring continued for 0.5 hour. The mixture was then cooled to −78° C. and 2,6-lutidine (3.76 mL, 32.3 mmol) was added slowly. The mixture was allowed to warm up to 0° C. and stirred for 0.5 hour. The mixture was then cooled to −78° C. before the slow addition of benzo[1,3]dioxole-5-carboxylic acid methoxy-methyl-amide (4.5 g, 21.5 mmol; see Example 2 above) in anhydrous THF (10 mL). The mixture was stirred at −78° C. for 0.5 hour, at 0° C. for 0.5 hour, and at room temperature for 2 hours. The mixture was then quenched with ammonium chloride aqueous solution and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. After purification using column chromatography on silica gel (eluent: ethyl acetate (2): hexanes (8)), 4.8 g (87%) of 1-Benzo[1,3]dioxol-5-yl-2-(6-methyl-pyridin-2-yl)-ethanone as a yellow solid was obtained. MS (ESP+) m/z 256.1 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.56 (t, 1H, J=7.5 Hz), 7.39 (dd, 1H, J=1.8 Hz, 8.3 Hz), 7.30 (dd, 1H, J=0.5 Hz, 1.8 Hz), 6.93 (m, 1H), 6.83 (m, 2H), 5.98 (s, 2H), 4.87 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:21]1([O:27][CH2:28][CH2:29][Br:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[Br-:30].[OH:10][C:9]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:29][CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:8][CH2:7]1)[CH2:2][CH2:3]2
Reactant: OC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Reactant: BrCCOc1ccccc1
Solvent: ClC(Cl)Cl
Product: OC(c1cccs1)(c1cccs1)C12CC[N+](CCOc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 71.5 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(di-2-thienyl)methanol (0.0693 g, 0.227 mmol) and 2-bromoethyl phenyl ether (0.056 g, 0.279 mmol) in 1MeOH/1 CHCl3 (3.0 mL) were reacted to give the desired product (0.0822 g, 74.7%). EI-MS m/z 426(M+) Rt (2.00 min).
Reaction SMILES: [N+]([O-])(O)=O.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15][C:16]([NH2:18])=[NH:17].CN(C)[CH:21]=[CH:22][C:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=O.[OH-].[Na+]>C(O)(C)C>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15][C:16]1[N:18]=[C:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][N:17]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Reactant: CN(C)C=CC(=O)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1

Procedure:
248.2 g (0.96 mol) of 2-methyl-5-nitrophenylguanidine nitrate are added to a solution of 170 g (0.96 mol) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one in 2.0 liters of isopropanol. After the addition of 42.5 g of sodium hydroxide, the reddish suspension is boiled at reflux for 12 hours. After cooling to 0°, filtration, washing with 2.0 liters of isopropanol and 3×400 ml of methanol and drying, there is obtained N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine, m.p. 195°-198°, Rf =0.68 (methylene chloride:methanol=9.1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[N-:13]=[N+]=[N-].[Na+].O.C(=O)([O-])O.[Na+]>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:13][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc2c(c1)CCNC2=O
Yield: 43 %

Procedure:
To a solution of 5-methoxy-1-indanone (1.0 g) in TFA (20 ml) is added sodium azide (4.0 g), and the mixture is refluxed for 1.5 hour. After cooling, the reaction mixture is poured into water (100 ml), and the pH value of the mixture is adjusted to pH 7 with sodium hydrogen carbonate. The mixture is extracted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, and dried over magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel; 100 g, chloroform/methanol=20:1). The fractions containing the title compound are concentrated under reduced pressure to give the title compound (470 mg) as a pale brown powder.
Reaction SMILES: I.[OH:2][CH:3]1[C@@H:7]([NH:8][C:9](=[O:32])[C@H:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:11][C:12](=[NH:27])[C:13]2[CH:26]=[CH:25][C:24]3[S:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]=3[CH:14]=2)[CH2:6][CH2:5][O:4]1.[Cl-:33]>O>[ClH:33].[OH:2][CH:3]1[C@@H:7]([NH:8][C:9](=[O:32])[C@H:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[NH:11][C:12](=[NH:27])[C:13]2[CH:26]=[CH:25][C:24]3[S:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]=3[CH:14]=2)[CH2:6][CH2:5][O:4]1
Reactant: [Cl-]
Agent: CC(C)C[C@H](NC(=N)c1ccc2c(c1)Nc1ccccc1S2)C(=O)N[C@H]1CCOC1O
Agent: I
Solvent: O
Product: Cl

Procedure:
A solution of 2.5 g (4.4 mmoles) of the compound of Example 5 in 1 liter of distilled water is deposited at the top of a column containing approximately 10 equivalents of a Dowex-1×2 exchange resin previously equilibrated in the chloride form. The compound is eluted dropwise from the column using distilled water. The fractions containing the expected compound are collected and lyophilized. 1.55 g (yield: 74%) of a yellow solid is obtained. Melting point: 202-205° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][O:5][CH2:6][CH2:7]O.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:34]I>CCOCC.CC#N>[CH3:1][O:2][C:3](=[O:9])[CH2:4][O:5][CH2:6][CH2:7][I:34]
Reactant: COC(=O)COCCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)COCCI
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To solution of methyl(2-hydroxyethoxy)acetate (540 mg), imidazole (411 mg) and triphenylphosphine (1.37 g) in ether (2 mL) and CH3CN (1 mL) was added iodine (1.43 g) under ice-water cooling and the mixture was stirred at 0° C. for 2 hours. After insolubles were filtered off, the filtrates were diluted with AcOEt, washed with aq Na2SO3 solution and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-5:1) to give methyl(2-iodoethoxy)acetate as colorless oil (898 mg).
Reaction SMILES: [ClH:1].Cl.N=C[O:5]CNCCC[C@@H](C(O)=O)N.N#N.Cl.C([O:23][C:24](=[O:43])[C@H:25]([CH2:34][CH2:35][CH2:36][NH:37][CH:38]=[N:39][O:40][CH2:41][CH3:42])[NH:26]C(OC(C)(C)C)=O)(C)(C)C>>[OH2:5].[ClH:1].[ClH:1].[CH2:41]([O:40][N:39]=[CH:38][NH:37][CH2:36][CH2:35][CH2:34][C@@H:25]([C:24]([OH:43])=[O:23])[NH2:26])[CH3:42]
Reactant: N=COCNCCC[C@H](N)C(=O)O
Reactant: CCON=CNCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: N#N
Product: CCON=CNCCC[C@H](N)C(=O)O
Product: O
Yield: 94 %

Procedure:
By the method described above for the preparation of N5 -(iminomethoxymethyl)-L-ornithine dihydrochloride, 0.78 g (1.97 mmol) N2 -(tert-butoxycarbonyl)-N5 -(ethoxyiminomethyl)-L-ornithine tert-butyl ester hydrochloride was deprotected to yield 0.51 g (94%) N5 -(ethoxyiminomethyl)-L-ornithine dihydrochloride monohydrate. TLC (silica gel, ammonium hydroxide:methanol/1:25) Rf=0.24. Mass spectrum (CI) 204 (MH+, 74%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
A solution of tert-butyl 4-(methylsulfonyl)piperazine-1-carboxylate (7 g) in methylene chloride (150 ml) containing TFA (35 ml) was stirred for 2 hours at ambient temperature. The volatiles were removed under vacuum and the resultant residue was partitioned between methylene chloride and 2N aqueous sodium hydroxide. The organic phase was separated and washed with brine, dried over magnesium sulphate and evaporated to give 1-(methylsulfonyl)piperazine (2.18 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][NH:14][CH3:15].O>CN(C)C=O>[CH3:13][N:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH3:15]
Reactant: CNC
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of methyl 4-bromomethylbenzoate (22.8 g) in N,N-dimethylformamide (450 ml) is added dropwise 50% aqueous dimethylamine solution (27 mL) and the mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into water with ice and extracted with ethyl acetate. The extract is washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant crude product is purified by flash column chromatography on silica gel (Solvent; chloroform:methanol=10:1) to give methyl 4-[(dimethylamino) methyl]benzoate (27.5 g, yield; 99%) as brown oil. MS (APCI) m/z: 194 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:28])([CH3:27])[CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)=[CH:6][CH:5]=1)[CH3:2].IC1C=C(C(C)(C)COCC2C=CC=C(OC3C=CC=CC=3)C=2)C=CC=1OCC>>[O:20]([C:16]1[CH:15]=[C:14]([CH3:13])[CH:19]=[CH:18][CH:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1.[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:27])([CH3:28])[CH2:11][OH:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1
Agent: CCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1I
Product: CCOc1ccc(C(C)(C)CO)cc1
Product: Cc1cccc(Oc2ccccc2)c1

Procedure:
An oily product was obtained by carrying out the post-treatment in the same manner as in Example 5. From the results of the analysis of the oily product by gas chromatography according to the internal standard method, it was found that the oily product comprised 99.2% of 3-phenoxybenzyl 2-(4-ethoxyphenyl)-2-methylpropyl ether and 0.1% of unreacted starting 3-phenoxybenzyl 2-(3-iodo-4-ethoxyphenyl)-2-methylpropyl ether, and that the content of each of 3-phenoxytoluene and 4-ethoxyneophyl alcohol formed by cleaving of the ether linkage was lower than 0.3%. The amount of the obtained oily product was 26.0 g and the yield was 95.1%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C=C/c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCc1cccc(N)c1
Reaction time: 16 h
Yield: 86 %

Procedure:
A Parr hydrogenation vessel was charged with Part (1) compound (12.0 g, 54.3 mmol), concentrated HCl (15 mL, 0.15 mmol), 10% palladium on carbon (750 mg) and absolute ethanol (75 mL). The slurry was purged with nitrogen and agitated under an initial pressure of 45 psi of hydrogen gas. After 16 h, the flask was evacuated and the contents filtered through Celite and evaporated. The residue was dissolved in water and adjusted to DH 9 with solid sodium carbonate. The resulting mixture was extracted with dichloromethane (250 mL×2). The combined extracts were evaporated to give the title compound (8.7 g, 86%) as an oil.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5]CC)OCC.[F:11][CH:12]([F:21])[C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=O>>[CH2:9]([O:8][C:1](=[O:5])/[C:14](=[CH:15]\[O:17][CH2:18][CH3:19])/[C:13](=[O:20])[CH:12]([F:21])[F:11])[CH3:10]
Reactant: CCOC(=O)CC(=O)C(F)F
Reactant: CCOC(OCC)OCC
Product: CCO/C=C(\C(=O)OCC)C(=O)C(F)F
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
Process step c): 778.1 g (5.25 mol) of triethyl orthoformate were charged in a stirred vessel, the pressure within the vessel was slowly reduced to 310 mbar and the triethyl orthoformate was heated to 104° C. 121.1 g (0.175 mol-100% conversion in process steps a) and b) assumed) of ethyl 4,4-difluoroacetoacetate (in the form of a suspension coming from process step b)) were added at 103° C. to 104° C. within 2 hours. Thereafter, the reaction mixture was stirred at 105° C. for further 30 minutes. During the entire reaction time low boiling compounds were removed by distillation under reduced pressure. Afterwards, the suspension was cooled down to room temperature. The resulting suspension (761 g) comprised 4.36% (w/w) of the desired product (GC analysis, quantification with internal standard). This corresponds to an overall yield over the two synthetic steps of 85.4%, based on ethyl difluoroacetate used.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[O:7])[N:4]([CH2:8][C:9](=O)[CH3:10])[N:3]=1.O.[NH2:13][NH2:14].O.O.C(O)(=O)C(O)=O>C(O)(C)C.O>[C:2]([NH:3][N:4]1[CH2:8][C:9]([CH3:10])=[N:14][NH:13][C:5]1=[O:7])(=[O:6])[CH3:1]
Reactant: NN
Reactant: CC(=O)Cn1nc(C)oc1=O
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CC(C)O
Product: CC(=O)NN1CC(C)=NNC1=O

Procedure:
To a solution of 156 g of 2,3-dihydro-5-methyl-2-oxo-1,3,4-oxadiazol-3-ylacetone in 600 ml of isopropanol and 15 ml of water, 75 g of hydrazine hydrate are added at 70° C. over a period of 30 minutes. The mixture is subsequently stirred at reflux temperature for a further 6 hours. 40 g of oxalic acid dihydrate in 160 ml of isopropanol are added, and the precipitate is filtered off, while the mixture is hot, and washed with 150 ml of isopropanol. The filtrate is evaporated in vacuo until the total volume is about 600 ml, then cooled to 0° C. to +5° C., and the precipitated product is filtered off and dried yielding 158 g (93% of the theoretical amount) of the title compound having a melting point of 199°-200° C.
Reaction SMILES: [Cl-].[Cl-].[CH-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Ti+2:13].C[Li]>CCOCC.O>[CH3:8][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C-:8]1([CH3:3])[CH:12]=[CH:11][CH:10]=[CH:9]1.[Ti+2:13]
Reactant: c1cc[cH-]c1
Agent: [Ti+2]
Agent: [Cl-]
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Product: C[c-]1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 197 %

Procedure:
A solution of 2.49 g (10.0 mmol) of titanocene dichloride in 50 ml of ether in the dark at 0° C. was treated with 17.5 ml of 1.4M methyllithium solution in ether maintaining the internal temperature below 5° C. The resulting yellow/orange mixture was stirred at room temperature for 30 minutes and the reaction was quenched by slowly adding 25 g of ice. The quenched reaction mixture was diluted with 50 ml of ether and 25 ml of water and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 2.03 g (98%) of the title compound as a light-sensitive solid. The dimethyl titanocene could be stored as a solution in toluene at 0° C. for at least 2 weeks without apparent chemical degradation. 1H NMR (200 MHz, CDCl3) δ -0.15 (6H, s), 6.06 (10H, s).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([S:10][CH2:11][CH2:12][CH3:13])[N:3]=1.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[NH2:24][C@H:25]1[C@@H:29]2[O:30][C:31]([CH3:34])([CH3:33])[O:32][C@@H:28]2[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]1.CS(C)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[NH2:8][C:7]1[C:2]([NH:24][C@H:25]2[C@@H:29]3[O:30][C:31]([CH3:33])([CH3:34])[O:32][C@@H:28]3[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]2)=[N:3][C:4]([S:10][CH2:11][CH2:12][CH3:13])=[N:5][C:6]=1[Cl:9]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCO)C[C@H]2N
Reactant: CCCSc1nc(Cl)c(N)c(Cl)n1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Temperature: 62.5 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
A flask was charged with 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (3 g), 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt (5.1 g), dimethyl sulfoxide (30 mL) and sodium bicarbonate (6.3 g). The mixture was heated to about 60-65° C. and maintained at the same temperature for about 10 hours and completion of the reaction was monitored by TLC. After completion of reaction the mixture was cooled to 25-30° C. followed by addition of water (30 mL) and toluene (30 mL). The mixture was stirred for about 10 minutes and layers were separated. The organic layer was with water (30 mL). The organic layer was separated and subjected to complete distillation under vacuum at 55-60° C. followed by cooling to room temperature and subsequent addition of n-hexane (45 mL). The mixture was stirred for about 3 hours at room temperature followed by isolation of solid by filtration and washing with n-hexane (15 mL). The solid isolated was subjected to drying under vacuum at 55-60° C. for about 4 hours to afford the title compound in about 78% yield having HPLC purity of about 98%.