Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].O1CCCC1.[CH:18]([C@@H:20]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:21][C@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=1)[CH:23]([CH3:25])[CH3:24])=[O:19]>CS(C)=O>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C@H:22]([CH:23]([CH3:24])[CH3:25])[CH2:21][C@H:20]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[C@@H:18]2[CH2:7][O:19]2)=[CH:28][C:29]=1[O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40]
Reactant: CC(C)(C)[O-]
Reactant: COCCCOc1cc(C[C@@H](C[C@@H](C=O)NC(=O)OC(C)(C)C)C(C)C)ccc1OC
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CO2)C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.87 g of trimethylsulphoxonium iodide and 1.98 g of potassium tert-butoxide are stirred under high vacuum overnight, admixed with 24 ml of tetrahydrofuran and subsequently cooled to 0° C. A solution of 4.00 g of tert-butyl {1(S)-formyl-3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]4-methylpentyl}carbamate [CAS 172900-83-3] in 24 ml of dimethyl sulphoxide is added dropwise. After 2 hours, the reaction mixture is partitioned between water and tert-butyl methyl ether and the aqueous phase is extracted once more with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water (3×) and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue first by means of flash chromatography (SiO2 60F) and then by means of crystallization (hexane) as white crystals. Rf=0.43 (1:1 EtOAc-heptane); Rt=21.90 (gradient II); m.p. 59-65° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([O:13]C)[C:8]([O:11]C)=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.Br>O>[CH2:1]([C:5]1[CH:6]=[C:7]([OH:13])[C:8](=[CH:9][CH:10]=1)[OH:11])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc(CC(C)C)cc1OC
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Cc1ccc(O)c(O)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 50.83 g (262 mM) of 4-isobutylveratrole, 167.82 g (2.795 mM) of acetic acid and 502.18 g (2.917 mM) of 47% hydrobromic acid was heated under reflux for 19 hours with stirring. The reaction mixture was cooled to the room temperature and added with 400 ml of water. The separated oil was extracted with ether. The ether solution was successively washed with 400 ml of water, 660 g of aqueous sodium thiosulfate solution, and further twice with each 400 ml of water. The resulting solution was dried with anhydrous sodium sulfate, distilled off ether, and vacuum distilled to obtain 35.68 g (215 mM) of 4-iso-butylcatechol as yellow viscous liquid having a boiling point of 117°-120° C./2 mmHg.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6](C(OC(C)(C)C)=O)[C:7]2[C:12]([CH:13]=1)=[C:11]([CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[CH:10]=[CH:9][CH:8]=2)=[O:4].[OH-].[Na+].Cl>C1COCC1>[N:15]1([CH2:14][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:12]=2[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[NH:6]3)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: COC(=O)c1cc2c(Cn3ccnc3)cccc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(Cn3ccnc3)cccc2[nH]1
Temperature: 80 °C
Reaction time: 48 h
Yield: 26.4 %

Procedure:
The mixture of 4-Imidazol-1-ylmethyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methy ester (350 mg, 0.99 mmol) and 2N aqueous sodium hydroxide solution (1 mL. 2 mmol) in THF (5 mL) was refluxed at 80° C. with stirring for 2 days. 2N hydrochloric acid was added until pH was 7.0. The mixture was concentrated in vacuo. The resulting percipitate was collected by filtration and washed with dichloromethane, methanol, H2O and ethyl acetate to give 63 mg (27% yield) of the title compound as a white solid:
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[Cl:5][C:6]1[C:7]([C:14]([O:16][CH3:17])=[O:15])=[N:8][C:9]([F:13])=[CH:10][C:11]=1F.O>CN(C)C=O>[NH2:1][C:11]1[CH:10]=[C:9]([F:13])[N:8]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[C:6]=1[Cl:5]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1nc(F)cc(F)c1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(F)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
Sodium azide (0.0086 mol, 0.60 g) was added to a solution of methyl 3-chloro-4,6-difluoropyridine-2-carboxylate (0.0072 mol, 1.5 g) in 15 mL dimethyl formamide (DMF). The solution was stirred 10 min at ambient temperature before pouring into 350 mL water and extracting the aqueous mixture with EtOAc (2×100 mL). The organic phase was dried (Na2SO4) and then treated with excess NaBH4 for 30 min. The excess NaBH4 was quenched with aqueous EtOH and the mixture was diluted with water (200 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×200 mL). The combined organic layers were dried (Na2SO4) and concentrated to an off-white powder which was purified by reversed-phase HPLC to give methyl 4-amino-3-chloro-6-fluoropyridine-2-carboxylate (0.0059 mol, 1.2 g). 1H NMR(CDCl3): δ 3.95 (3H, s), 5.2-5.1 (2H, bs), 6.36 (1H, s). 19F NMR {1H}: δ −72.7.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[CH:5]([CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[NH2:6].[CH2:14]([O:21][C:22]([NH:24][C@H:25]([C:37](O)=[O:38])[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[CH3:2][O:3][C:4](=[O:13])[CH:5]([CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[NH:6][C:37](=[O:38])[C@H:25]([CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)[NH:24][C:22]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23]
Reactant: O=C(N[C@@H](Cc1cccc2ccccc12)C(=O)O)OCc1ccccc1
Reactant: COC(=O)C(N)Cc1cccs1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1cccs1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 73.6 %

Procedure:
A mixed solution of 1.11 g (5 mmole) of 3-(2-thienyl)-DL-alanine methyl ester hydrochloride and 1.75 g (5 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanine in 15 ml of dimethylformamide was cooled with ice water, and then 1.11 g (11 mmole) of triethylamine was added with stirring. After that, 0.83 g (5 mmole) of diethyl phosphorocyanidate was added, and the mixture was stirred for 3 hours at room temperature. Subsequently, the reaction product was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water, then dried, and finally purified by thin layer chromatography, yielding 1.9 g (73.6%) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(2-thienyl)-DL-alanine methyl ester melting at 140°-141° C.
Reaction SMILES: [C:1]([C@@H:3]([NH:19][C:20]([C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23]1C(OC(C)(C)C)=O)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)#[N:2]>C(O)=O>[C:1]([C@@H:3]([NH:19][C:20]([C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][NH:23]1)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@H](C#N)Cc1ccc(-c2ccc(C#N)nc2)cc1
Solvent: O=CO
Product: N#Cc1ccc(-c2ccc(C[C@@H](C#N)NC(=O)[C@@H]3CCCCN3)cc2)cn1
Yield: 82.9 %

Procedure:
(S)-tert-Butyl 2-((S)-1-cyano-2-(4-(6-cyanopyridin-3-yl)phenyl)ethylcarbamoyl)-piperidine-1-carboxylate (0.074 g) in formic acid (3 mL) was heated at 50° C. for 10 min. The mixture was evaporated, dissolved in methanol and applied to a 10 g SCX column. The column was washed with methanol then eluted with 10% ammonia in methanol. The eluate was evaporated. The residue was triturated with isopropanol and the solid collected, washed with a little isopropanol and diethyl ether then dried to leave the title compound as a solid (0.048 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[F-:13].[K+].O>CC(N(C)C)=O>[F:13][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=Cc1cc(F)ccc1[N+](=O)[O-]
Yield: 71 %

Procedure:
37 g (0.2 mol) of 5-chloro-2-nitrobenzaldehyde and 23.2 g (0.4 mol) of potassium fluoride in 300 ml of dimethylacetamide are stirred for 3 hours at 150° C. The solvent is then stripped off in vacuo and the residue is stirred with 200 ml of water. The aldehyde is extracted with methylene chloride, and the organic phase is separated off, dried and evaporated down. 24 g of 5-fluoro-2-nitrobenzaldehyde with a content of 86% are obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:57])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:54])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:53])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42](=[O:52])[NH:43][C@H:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=4)[CH3:45])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:56])[CH3:55])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].[C:58]([OH:64])([C:60]([F:63])([F:62])[F:61])=[O:59]>ClCCl>[CH:37]([C:33]1[C:34](=[O:36])[CH2:35][C@:23]2(/[CH:40]=[CH:41]/[C:42](=[O:52])[NH:43][C@H:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[CH3:45])[CH2:22][CH2:21][C@:20]3([CH3:53])[C@H:25]([CH2:26][CH2:27][C@H:28]4[C@@:19]3([CH3:54])[CH2:18][CH2:17][C@@H:16]3[C@:29]4([CH3:32])[CH2:30][CH2:31][C@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:57])[C:3]([OH:5])=[O:4])[C:15]3([CH3:55])[CH3:56])[C:24]=12)([CH3:38])[CH3:39].[F:61][C:60]([F:63])([F:62])[C:58]([OH:64])=[O:59]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2ccccn2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2ccccn2)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3a-((E)-3-oxo-3-(((S)-1-(pyridin-2-yl)ethyl)amino)prop-1-en-1-yl)-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (480 mg, 0.611 mmol) in dichloromethane (10 mL) stirred at rt was added TFA (5 mLl). The reaction mixture was stirred at rt for 2 h. Then, it was evaporated in vacuo to get crude product. This material was purified by preparative-HPLC to provide the title compound as a trifluoroacetic acid salt (220 mg, 0.261 mmol, 42.7%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=9.43 (d, J=7.0 Hz, 1H), 8.75 (d, J=4.5 Hz, 1H), 8.33 (t, J=7.7 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.77 (t, J=6.4 Hz, 1H), 6.77 (d, J=15.8 Hz, 1H), 5.89 (d, J=15.8 Hz, 1H), 5.50-5.27 (m, 1H), 4.50 (dd, J=5.3, 10.8 Hz, 1H), 3.29-3.05 (m, 1H), 2.76-2.44 (m, 3H), 2.31-2.00 (m, 3H), 2.03-0.51 (m, 47H); LC/MS: m/z calculated 728.5. Found 729.3 (M+1)+.
Reaction SMILES: [CH2:1]([C:3]([C:8]1[C:9]([CH3:14])=[N:10][CH:11]=[CH:12][CH:13]=1)([O:6][CH3:7])[CH2:4][CH3:5])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:16].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[CH2:1]([C:3]([C:8]1[C:9]([CH2:14][OH:16])=[N:10][CH:11]=[CH:12][CH:13]=1)([O:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCC(CC)(OC)c1cccnc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCC(CC)(OC)c1cccnc1CO
Reaction time: 24 h
Yield: 60 %

Procedure:
To a solution of 3-(1-ethyl-1-methoxy-propyl)-2-methyl-pyridine (0.185 g, 0.884 mmol) in CH2Cl2 (3 mL) was added TFAA (1 mL). The mixture was stirred for 24 h. K2CO3 (0.60 g, 4.3 mmol) in water (10 mL) was added. The aqueous mixture was extracted with CH2Cl2 (4×25 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (3:1 Et2O/CH2Cl2), affording [3-(1-ethyl-1-methoxy-propyl)-pyridin-2-yl]-methanol as a yellow oil (0.111 g, 60%). 1H NMR (CDCl3) δ 0.70 (t, 6H, J=7.5 Hz), 1.76-1.88 (m, 2H), 1.89-2.01 (m, 2H), 3.06 (s, 3H), 4.93 (s, 2H), 7.21 (dd, 1H, J=7.8, 4.8 Hz), 7.56 (dd, 1H, J=7.8, 1.5 Hz), 8.47 (dd, 1H, J=4.8, 1.5 Hz).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[S:7][CH:8]=[CH:9][C:10]=2[NH2:11])[N:3]=[CH:2]1.[O:12]=[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:19]=2)[N:14]1[CH2:27][C:28](O)=[O:29]>>[O:12]=[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]([F:25])([F:24])[F:26])[CH:19]=2)[N:14]1[CH2:27][C:28]([NH:11][C:10]1[CH:9]=[CH:8][S:7][C:6]=1[C:4]1[N:3]=[CH:2][S:1][CH:5]=1)=[O:29]
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Reactant: Nc1ccsc1-c1cscn1
Product: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)ccc21)Nc1ccsc1-c1cscn1

Procedure:
The title compound was prepared from 2-(thiazol-4-yl)thiophen-3-amine and 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid according to protocol A. Retention time (min)=6.485, method [7], MS(ESI) 436.1 (M+H); 1H NMR (300 MHz, CD3Cl) δ 11.32 (s, 1H), 8.51 (d, J=1.5 Hz, 1H), 8.04 (d, J=5.5 Hz, 1H), 7.92 (d, J=10.2 Hz, 1H), 7.90 (s, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.22 (d, J=1.4 Hz, 1H), 7.20 (d, J=5.5 Hz, 1H), 7.03 (d, J=9.7 Hz, 1H), 5.23 (s, 2H).
Reaction SMILES: [C:1](=[O:9])([O:7][CH3:8])[O:2][CH2:3][CH:4]([F:6])[F:5].[C:10](Cl)(=O)OCC.C(Cl)(=O)OC>>[C:1](=[O:9])([O:7][CH2:8][CH3:10])[O:2][CH2:3][CH:4]([F:6])[F:5]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)OCC(F)F
Agent: COC(=O)Cl
Product: CCOC(=O)OCC(F)F

Procedure:
2,2-Difluoroethyl ethyl carbonate was prepared as in [Synthesis of 2,2-Difluoroethyl Methyl Carbonate] of Example IV-1, except that ethyl chlorocarbonate (7.9 g, 0.073 mol) was substituted for methyl chlorocarbonate (6.9 g, 0.073 mol).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16]CC)=[O:15])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O1CCCC1>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([OH:16])=[O:15])=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2cc(C(C)(C)C)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2[nH]c(C(=O)O)cc2c1
Yield: 93 %

Procedure:
A solution of ethyl 5-tert-butylindole-2-carboxylate (3.0 g) and 1N sodium hydroxide solution into a mixed solvent of tetrahydrofuran (20 ml) and methanol (10 ml) was stirred at 40° C. for 5 hours. After removal of solvent, the resulting aqueous solution was made acidic with diluted hydrochloric acid. The resulting precipitates were collected by filtration and washed with water to give 5-tert-butylindole-2-carboxylic acid (2.47 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:21]([O:23][C:24](=[O:38])[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[CH3:22].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[CH3:37][O:36][C:29]1[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:28]=1[CH2:27][N:26]([CH2:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:38]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1onc(-c2ccc(OC)cc2)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(-c2ccc(OC)cc2)noc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
Ethyl 4-(bromomethyl)-3-(4-methoxyphenyl)isoxazole-5-carboxylate (47.5 mmol) was dissolved in 100 mL of DMF. N-(2,4-dimethoxybenzyl)glycine ethyl ester (12.0 g, 47.5 mmol) and potassium carbonate (7.2 g, 41.6 mmol) were added, and the mixture was stirred at room temperature for 16 h. EtOAc (200 mL) and brine (200 mL) were added and the aqueous layer was extracted with additional EtOAc. The combined organic layer was washed with water and brine, and dried over MgSO4. After solvent was removed in vacuo, the crude was purified by flash chromatography (0-35% EtOAc/hexanes) to give 13.7 g of the title compound. 1H NMR (CDCl3, 200 MHz): δ=8.00 (d, 2H, J=8.8 Hz), 7.06-7.15 (m, 1H), 6.93 (d, 2H, J=8.8 Hz), 6.30-6.50 (m, 2H), 4.47 (q, 2H, J=7.4 Hz), 4.10-4.22 (m, 2H), 3.70-3.90 (m, 9H), 3.66 (s, 4H), 3.31 (s, 2H), 1.43 (t, 3H, J=7.0 Hz), 1.20-1.40 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C[N:11](N=O)[C:12]([NH:14][N+:15]([O-:17])=[O:16])=N.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:12]([NH:14][N+:15]([O-:17])=[O:16])=[NH:11]
Reactant: NCc1cccc(F)c1
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(NCc1cccc(F)c1)N[N+](=O)[O-]
Reaction time: 18 h
Yield: 89.2 %

Procedure:
The compound m-fluorobenzylamine (7.5 g, 0.06 mol) is added to a slurry of N-methyl-N-nitroso-N'-nitroguanidine (8.33 g, 0.056 mol) in a 50% aqueous ethanol mixture. The thus-formed mixture is stirred for 18 hours, then treated with 1N NaOH (150 ml), and the mixture filtered. The filtrate is acidified with concentrated HCl, and the reaction mixture is then filtered to obtain the desired fluffy white solid product (10.6 g) having a melting point of 177° C. -179° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-:23][Si](C)(C)C)(C)C.[ClH:28]>C1COCC1>[ClH:28].[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]([NH2:23])=[NH:14])=[C:11]([F:17])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(OCc2ccccc2)cc1F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: N=C(N)c1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
A solution of 4-benzyloxy-2-fluoro-benzonitrile (84 g, 0.37 mol) in THF (450 mL) under an atmosphere of nitrogen, was cooled to −70° C. The resultant suspension was treated with a solution of 1M LiHMDS in THF (440 mL, 0.44 mol) over 10 min to reach a maximum temperature of −55° C. The reaction mixture was allowed to warm to RT and stirred for three days. Reaction progress was monitored by TLC analysis. The reaction mixture was poured onto ice/1M HCl mixture, the pH adjusted to ˜1 by addition of 6M HCl and washed with EtOAc (500 mL). The organic layer was extracted with 1M HCl and the combined aqueous extracts washed with EtOAc (500 mL). The acid aqueous extracts were concentrated to low volume in vacuo and the resultant solid filtered off, washed with H2O and dried in vacuo to give 4-Benzyloxy-2-fluoro-benzamidine hydrochloride as a pale cream crystalline solid (74.5 g, 72%). 1H NMR (400 MHz, d6-DMSO): 9.30 (4H, d, J=10.39 Hz), 7.64 (1H, t, J=8.59 Hz), 7.49-7.35 (5H, m), 7.19 (1H, dd, J=12.88, 2.41 Hz), 7.06 (1H, dd, J=8.77, 2.41 Hz), 5.25 (2H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:17]=[O:18].[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.O1CCCC1.Cl.O>O1CCCC1>[CH:19]1([CH:17]([C:3]2[S:4][C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=3)=[CH:6][C:2]=2[CH3:1])[OH:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a solution of 3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde (0.8 g) in tetrahydrofuran (20 mL) was added dropwise 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (5 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 30 min. The reaction mixture was treated with 1N hydrochloric acid and poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (0.5 g, 51%) as a yellow crystal.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH2:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([Cl:19])[N:13]=1>C1COCC1>[NH2:11][C:12]1[N:17]=[C:16]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[C:14]([Cl:19])[N:13]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(Cl)cc(OCc2ccccc2)n1
Reaction time: 0.42 h

Procedure:
To 30 ml of a THF solution of 1.35 ml of benzyl alcohol cooled to 0° C. was added 480 mg of sodium hydride (60% oil dispersion) in a nitrogen atmosphere. After the mixture was stirred at the same temperature for 25 minutes, 1.64 g of 2-amino-4,6-dichloropyrimidine was added thereto, followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated to dryness, and 100 ml of water was added to the residue. The precipitate was collected by filtration to obtain 2.36 g of 2-amino-4-benzyloxy-6-chloropyrimidine as white powder. To the powder was added 30 ml of ethanol, and 3.11 ml of hydrazine monohydrate and 1.38 g of potassium carbonate were added thereto, followed by heat-refluxing for 21 hours. After cooling to room temperature, the reaction mixture was concentrated. Water was added to the residue, and the precipitate was collected by filtration to give 1.95 g of white powder. To the powder were added 30 ml of ethanol and then 1.57 g of ethyl ethoxymethyleneacetoacetate, and the mixture was stirred at room temperature for 1 hour and then refluxed for 5 hours. The reaction mixture was cooled to room temperature, and the solvent was removed by evaporation. The residue was purified by silica gel column chromatography using hexane-ethyl acetate (1:1 by volume) as a developing solvent. The fraction containing the desired compound was concentrated to give 1.72 g of the title compound.
Reaction SMILES: C(NCC)C.[CH2:6]([O:8][C:9](=[O:30])[CH:10]([CH:14]([C:16]1[CH:17]=[N:18][C:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:20][CH:21]=1)[CH3:15])[C:11](O)=O)[CH3:7].C=O.CCOC(C)=O>C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:30])[C:10]([CH:14]([C:16]1[CH:17]=[N:18][C:19]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])=[CH:20][CH:21]=1)[CH3:15])=[CH2:11])[CH3:7]
Reactant: CCOC(=O)C(C(=O)O)C(C)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: C=O
Solvent: CCNCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=C(C(=O)OCC)C(C)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Yield: 41.1 %

Procedure:
Diethylamine (0.153 mL, 1.473 mmol) was added to a solution of 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-ethyl]-malonic acid monoethyl ester (423 mg, 1.2 mmol) and formaldehyde (132 mg, 1.626 mmol, 36% in water) in methylene chloride (2 mL) at 0° C. under argon. The mixture was stirred at room temperature over night. EtOAc was added and the solution was washed with water, NaHCO3 and brine, dried and concentrated under reduced pressure. Flash chromatography (toluene/EtOAc, 3:1) gave 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-ethyl]-acrylic acid ethyl ester (158 mg, 41%).