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.[Cl:32][C:33]1[C:34]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:42][CH:41]=2)=[N:35][CH:36]=[C:37]([OH:39])[CH:38]=1.[CH2:55](O)[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]>O1CCCC1>[Cl:32][C:33]1[C:34]([C:40]2[CH:41]=[CH:42][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:44][CH:45]=2)=[N:35][CH:36]=[C:37]([O:39][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH:38]=1
Reactant: CCCCCCCCO
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cc2Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ncc(OCCCCCCCC)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
0.6 ml (3.8 mmol) of diethyl azodicarboxylate is added dropwise at 0° C. to 1.00 g (3.80 mmol) of triphenylphosphine in 15 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 minutes. 0.78 g (2.5 mmol) of 3-chloro-5-hydroxy-2-(4-octyloxyphenyl)-pyridine and 0.6 ml (3.8 mmol) of 1-octanol are subsequently added. After a reaction time of 18 hours at room temperature, the solvent is removed by distillation and the residue is purified by chromatography (silica gel, dichloromethane). Recrystallization from acetonitrile gives 0.63 g of 3-chloro-5-octyloxy-2-(4-octyloxyphenyl)pyridine. ##STR19## The compound has the phase sequence: X 32.2 (6.5) N 17 I.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].Br[CH2:15][C:16]([C:18]1[CH:22]=[C:21]([CH3:23])[S:20][C:19]=1[CH3:24])=O>>[CH3:24][C:19]1[S:20][C:21]([CH3:23])=[CH:22][C:18]=1[C:16]1[N:2]=[C:1]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[S:3][CH:15]=1
Reactant: Cc1cc(C(=O)CBr)c(C)s1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Product: COC(=O)c1ccc(-c2nc(-c3cc(C)sc3C)cs2)cc1
Yield: 64 %

Procedure:
In the same manner as in Example 74, methyl 4-thiocarbamoylbenzoate was reacted with 3-bromoacetyl-2,5-dimethylthiophene to obtain methyl 4-[4-(2,5-dimethyl-3-thienyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 64%. Pale yellow pritsms. Melting point: 109 to 110° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:25][CH:26]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1-c1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 78 %

Procedure:
A solution of 4-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol (1.00 g, 2.82 mmol), 1-bromooctane (0.584 ml, 3.38 mmol) and potassium carbonate (466 mg, 3.38 mmol) in DMF (20 ml) was stirred at 80° C. for 4 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.03 g (yield: 78.0%)
Reaction SMILES: C([O:5][C:6](=[O:17])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][N:10]=1)(C)(C)C.[OH-].[K+].[CH3:20][C@H:21]1[N:26]([CH3:27])[C@@H:25]([CH3:28])[CH2:24][N:23]([C:29]2[CH:30]=[C:31]([C:35](=[O:37])[CH3:36])[CH:32]=[CH:33][CH:34]=2)[CH2:22]1>CCO>[O:37]=[C:35]([C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([N:23]2[CH2:22][C@H:21]([CH3:20])[N:26]([CH3:27])[C@H:25]([CH3:28])[CH2:24]2)[CH:30]=1)/[CH:36]=[CH:15]/[C:12]1[CH:13]=[CH:14][C:9](/[CH:8]=[CH:7]/[C:6]([OH:5])=[O:17])=[N:10][CH:11]=1
Reactant: CC(=O)c1cccc(N2C[C@@H](C)N(C)[C@@H](C)C2)c1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1CN(c2cccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)c2)C[C@H](C)N1C
Temperature: 0 °C
Reaction time: 6 h
Yield: 96.9 %

Procedure:
A mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (described in Example 11 STEP A-D, 168 mg, 0.718 mmol), 1.7 M KOH (0.674 ml) and 1-[3-((3R,5S)-3,4,5-trimethyl-piperazin-1-yl)-phenyl]-ethanone (described in Preparation 8, 188 mg, 0.764 mmol) in EtOH (7 ml) was stirred at 0° C. for 6 h. The resulting precipitate was filtered off and dissolved in DCM (5 ml) and TFA (1 ml). The mixture was stirred at room temperature for 4 h and then the solvent was removed in vacuo to give 282 mg of (E)-3-(5-{(E)-3-oxo-3-[3-((3R,5S)-3,4,5-trimethyl-piperazin-1-yl)-phenyl]-propenyl}-pyridin-2-yl)-acrylic acid as its bis-trifluoroacetate salt.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][CH2:12][O:13][CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:21]([S:28][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][CH2:12][O:13][CH3:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: SCc1ccccc1
Reactant: COCCc1cc([N+](=O)[O-])ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCc1cc([N+](=O)[O-])ccc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
To a solution of 1-bromo-2-(2-methoxyethyl)-4-nitrobenzene (7.8 g, 30 mmol) and Cs2CO3 (14.66 g, 45 mmol) in DMF (100 mL) was added BnSH (4.1 g, 33 mmol) slowly, followed by stirring at room temperature for three hours. Water was added, the precipitate was filtered, washed by water and petroleum to give benzyl(2-(2-methoxyethyl)-4-nitrophenyl)sulfane (8 g, yield 88%). 1H NMR: 400 MHz CDCl3 δ 8.05 (s, 1H), 8.01-7.98 (m, 1H), 7.38-7.28 (m, 6H), 4.23 (s, 2H), 3.64-3.61 (m, 2H), 3.34 (s, 3H), 3.03-2.99 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][CH2:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.ClC(Cl)(Cl)C([N:40]=C=O)=O>ClCCl>[CH2:1]([O:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:40])[C:12]=2[N:11]=[C:10]1[CH2:22][CH2:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCCc1nc2cnc3ccccc3c2n1OCc1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3ccccc3c2n1OCc1ccccc1
Temperature: 0 °C
Yield: 40.7 %

Procedure:
A solution of 1-(benzyloxy)-2-propyl-1H-imidazo[4,5-c]quinoline (2.6 g, 8.2 mmol) in dichloromethane (100 mL) was cooled to approximately 0° C., and 3-chloroperoxybenzoic acid (3.6 g of approximately 77% pure material, 16 mmol) was added over a period of several minutes. The reaction was stirred for ten minutes at 0° C., stirred for 90 minutes at room temperature, washed with saturated aqueous sodium bicarbonate (2×35 mL, containing 1 mL of 25% w/w aqueous sodium hydroxide), dried over potassium carbonate, and filtered. The resulting solution was cooled to 0° C., and trichloroacetyl isocyanate (1.22 mL, 10.3 mmol) was added with stirring. The reaction was stirred for 15 minutes at 0° C., stirred for 75 minutes at room temperature, and concentrated under reduced pressure. The residue was dissolved in methanol (60 mL), and sodium methoxide (6.3 mL of a 25% w/w solution in methanol, 29 mmol) was added with stirring. The mixture was stirred at room temperature overnight. A precipitate formed, and the reaction mixture was cooled to approximately 0° C. The precipitate was collected by filtration, recrystallized from methanol/water, and dried overnight in a vacuum oven at 70° C. to provide 1.11 g of 1-(benzyloxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as white crystals, mp 164-166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:18][C:19]([CH3:21])=O.C(O)(=O)C>CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:10][CH2:11][CH:12]([NH:15][CH:19]([CH3:21])[CH3:18])[CH2:13][CH2:14]3)[S:8][C:4]=2[CH:3]=1
Reactant: NC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Reactant: CC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
A mixture of 1-(6-chlorobenzothiazole-2-yl)piperidine-4-ylamine (335 mg), acetone (92 ul), acetic acid (0.1 mL) and methanol (3 mL) was stirred at room temperature for 5 minutes. To the reaction solution was added triacetoxy sodium boron hydride (332 mg). The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. Aqueous sodium hydrogencarbonate was added thereto and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (160 mg). Yield: 41%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[N+:11]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH2:2][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7]#[N:8])([O-:13])=[O:12]
Reactant: C1CCNC1
Reactant: N#Cc1ccc(CBr)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(CN2CCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.9 %

Procedure:
To a stirred solution of 4-(bromomethyl)-3-nitrobenzonitrile (5.12 g, 21.57 mmol) and pyrrolidine (1.84 g, 25.88 mmol) in CH2Cl2 (72 mL) was added triethylamine (6.54 g, 64.71 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 1.5 h and evaporated to dryness under reduced pressure. The residue was diluted with water (30 mL) and extracted with CH2Cl2 (3×100 mL). The CH2Cl2 solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 3-nitro-4-(pyrrolidin-1-ylmethyl)benzonitrile (2.24 g, 45%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.16 (d, 1 H, J=1.6 Hz), 7.94 (br d, 1H, J=8.0 Hz), 7.83 (dd, 1H, J=8.0, 1.6 Hz), 3.99 (s, 2H), 2.54 (br s, 4H), 1.79 (m, 4H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH3:16])[CH:9]=1)=[O:7]>CCOCC>[CH2:15]([O:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][O:4][CH3:3])[CH:13]=[CH:12][CH:11]=1)[CH3:16]
Reactant: CCOc1cccc(C(=O)CO)c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CCOc1cccc(C(=O)COC)c1
Yield: 65 %

Procedure:
Boron trifluoride-diethyl ether complex (3 drops) and an ether solution of diazomethane were added to a solution of 2-hydroxy-3′-ethoxyacetophenone (1.6 g, 8.9 m mol) in ether (60 ml). The ether solution of diazomethane was added until thin-layer reveals that the spot of 2-hydroxy-3′-ethoxyacetophenone has disappeared. After insoluble matter was filtered off, the filtrate was concentrated under reduced pressure. The resulting residue was subjected to chromatography on silica gel (40 g) using ethyl acetate-hexane (1:4). Thus, the desired compound (1.13 g, 65%) was obtained as a colorless oily material.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[NH:7][C:6]=2[CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: Cc1c(Cl)cccc1CBr
Reactant: O=[N+]([O-])c1cc(Br)c2nc(CF)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1Cn1c(CF)nc2c(Br)cc([N+](=O)[O-])cc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
Into a 250 ml flask with 4-bromo-2-(fluoromethyl)-6-nitro-1H-benzo[d]imidazole (3 g, 10.95 mmol) in N,N-Dimethylformamide (DMF) (100 mL) was added 1-(bromomethyl)-3-chloro-2-methylbenzene (3.60 g, 16.42 mmol) and potassium carbonate (4.54 g, 32.8 mmol). The resulting reaction mixture was stirred 1 h at 80° C., cooled to room temperature and poured into water, extracted with ethyl acetate, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified on a silica gel cartridge and eluted with a gradient of 0% ethyl acetate/hexanes to 80% over 10 column volumes. The expected compound was collected and evaporated to yield 4-bromo-1-(3-chloro-2-methylbenzyl)-2-(fluoromethyl)-6-nitro-1H-benzo[d]imidazole (1.23 g, 2.98 mmol, 27.2% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.48 (s, 3H) 5.71 (s, 1H) 5.83 (s, 1H) 5.85 (s, 2H) 6.10 (d, J=7.58 Hz, 1H) 7.05 (t, J=7.83 Hz, 1H) 7.38 (d, J=7.83 Hz, 1H) 8.39 (d, J=2.02 Hz, 1H) 8.67 (d, 1H); LC/MS: MS (ES+) m/e 413 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[CH:28](=[O:32])/[CH:29]=[CH:30]/[CH3:31].Cl>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH:30]([CH3:31])[CH2:29][CH:28]=[O:32])=[O:15])[CH3:14]
Reactant: CCOP([O-])CCCCc1ccccc1
Reactant: C/C=C/C=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(CCCCc1ccccc1)C(C)CC=O
Temperature: 0 °C
Yield: 92 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (0.5 g, 0.0022 mole) in chloroform (15 ml) was added triethylamine (0.34 ml, 0.0024 mole), trimethyl silylchloride (0.30 ml, 0.0024 mole) and crotonaldehyde (0.20 ml, 0.0024 mole). The reaction mixture was stirred at reflux temperature for 18 hours; the mixture was poured into crushed ice (15 gm) containing 10 ml 5% HCl acid. It was shaken in a separatory funnel; a chloroform layer was evaporated, and the aqueous layer extracted once with 20 ml chloroform. The combined organic phase was washed with water, dried over anhydrous sodium sulphate and the organic solvent removed on a rotavap to produce the title compound as a yellow oil (0.60 g).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([OH:14])=[O:13])[NH:9]2)=[CH:5][CH:4]=1)#[N:2].[NH2:15][OH:16]>CCO>[NH2:2][C:1](=[N:15][OH:16])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([OH:14])=[O:13])[NH:9]2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccc2cc(C(=O)O)[nH]c2c1
Reactant: NO
Solvent: CCO
Product: NC(=NO)c1ccc2cc(C(=O)O)[nH]c2c1
Temperature: 60 °C
Yield: 104.2 %

Procedure:
A solution of 6-cyano-1H-indole-2-carboxylic acid (prepared according to J. Org. Chem. 1953, 18, 345-357, 1 g; 5.37 mmol; 1 eq.), hydroxylamine (50% in water; 1.77 mL; 26.86 mmol; 5 eq.) in EtOH (10 mL) was stirred at RT for 14 hours after which it was further heated at 60° C. for 28 hours. Solvents were removed under vacuum to give the title compound as a white powder (1.227 g; quantitative yield). 1H NMR (DMSO-d6) δ 11.75 (s, 1H), 7.72 (s, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.37 (dd, J=1.2, 8.5 Hz, 1H), 7.00 (d, J=1.2 Hz, 1H), 5.76 (bs, 2H), 3.44 (q, J=7.1 Hz, 2H), 1.05 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[N:21]1[CH2:26][CH2:25]O[CH2:23][CH2:22]1.ClC(OCC(C)C)=O.N1CCCC1>C1COCC1>[O:19]=[C:17]([N:21]1[CH2:26][CH2:25][CH2:23][CH2:22]1)[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccncc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccncc1)C(=O)N1CCCC1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 27.5 %

Procedure:
To a solution of N-Boc-(2S)-3-(pyridin-4-yl)alanine (500 mg, 1.9 mmol) in THF (12 mL) was added N-methylmorpholine (200 μL, 1.9 mmol) and the solution was stirred for 5 min, cooled at −15° C. and treated dropwise with isobutyl chloroformate (249 μL, 1.9 mmol). The mixture was stirred for 10 min and pyrrolidine (1.08 g, 15.2 mmol) was added and allowed to warm to 25° C. with stirring for 3 h. The solvent were removed under reduced pressure and the residue was partitioned between EtOAc and NaH2PO4 pH=7.2. The aqueous layer was discarded and the organic layer was washed with aqueous saturated NaHCO3, dried over Na2SO4, filtered and evaporated. The resulting solid was purified by column chromatography (SiO2) with a gradient of 0% to 10% [v/v] MeOH in EtOAc to give tert-butyl(S)-1-oxo-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-2-ylcarbamate EBE 06190 (167 mg, 28% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C1(N(C)C2CCCCC2)CCCCC1.[CH3:39][Si:40]([CH2:43][CH2:44][O:45][CH2:46]Cl)([CH3:42])[CH3:41]>O1CCCC1>[CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:46][O:45][CH2:44][CH2:43][Si:40]([CH3:42])([CH3:41])[CH3:39])[N:9]=2)[CH:5]=[C:4]([CH2:11][CH:12]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([O:15][CH3:16])=[O:14])[CH:3]=1
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)Cc1cc(C)c2[nH]ncc2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)C(CC(=O)OC(C)(C)C)Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1
Reaction time: 8 h

Procedure:
To a solution of 4-tert-butyl 1-methyl 2-((7-methyl-1H-indazol-5-yl)methyl)succinate (0.6053 g, 1.82 mmol) and N-cyclohexyl-N-methylcyclohexanamine (0.4686 mL, 2.19 mmol) in tetrahydrofuran (10 mL) was added trimethylsilylethoxymethyl chloride (0.3859 mL, 2.19 mmol) at room temperature under nitrogen. The reaction was stirred overnight and the solvent was removed in vacuo. The crude product was taken up in ethyl acetate (10 mL) and washed with water (3×5 mL). The ethyl acetate layer was dried, filtered and concentrated. The final product was obtained by flash chromatography, eluting with 0% to 20% ethyl acetate/hexane. (0.5873 g, 70%) HPLC tR=1.89 min, MS(ESI)[M+H]+=462.94.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[CH:4][CH:3]=1.[N:19](OC(C)(C)C)=[O:20].Cl>C(O)C.C(O)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])/[C:9](=[N:19]\[OH:20])/[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)ON=O
Reactant: CSc1nccc(CC(=O)c2ccc(F)cc2)n1
Agent: Cl
Solvent: CCO
Solvent: CCCO
Product: CSc1nccc(/C(=N/O)C(=O)c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(4-fluorophenyl)-2-(2-(methylthio)pyrimidin-4-yl)ethanone, 73 (1.0 g) in ethanol (20 mL) at −10° C., under an atmosphere of nitrogen, is added dropwise t-butyl nitrite (0.5 mL) followed by hydrogen chloride in n-propanol (2.5 to 3 N, 0.6 mL) while maintaining the temperature below −5° C. Once the addition is complete, the solution is allowed to warm to room temperature with stirring and after 2 h the solvent is evaporated and the residue partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The layers are separated; the aqueous phase is extracted with ethyl acetate and the combined organic phases dried over sodium sulfate. Filtration and evaporation of the solvent affords the title compound, 74 (1.0 g).
Reaction SMILES: C(O)C.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:11]([O:18][NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH2:11]([O:18][N:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C(=NOCc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 112.9 %

Procedure:
To a mixture of ethanol (100 mL), potassium carbonate (8.98 g, 65 mmol), and O-benzylhydroxylamine hydrochloride (10.0 g, 62.7 mmol) was added benzaldehvde (6.65 g, 62.7 mmol). The mixture was refluxed for 5 hours, allowed to cool to room temperature, and diluted with water (500 mL). The aqueous solution was extracted with ethyl acetate (500 mL). The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to give the title compound as a yellow oil (14.96 g, 119%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C([Li])CCC.CN(C)[CH:22]=[O:23].COC(C)(C)C>C1COCC1>[CH:22]([C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1)=[O:23]
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(C=O)cn1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of N-(5-Bromo-pyridin-2-yl)-2,2-dimethyl-propionamide (8.7 g, Kelly, Tetrahedron Lett., 32, 1991, 4263) in THF (200 mL) was cooled to −70° C. under an argon atmosphere and treated dropwise over 30 minutes with n-butyllithium (45.78 mL, 1.6 M in hexane, Acros). The mixture was stirred 1 h at −70° C. and then treated dropwise (over 10 minutes, at −70° C.) with a mixture of N,N-dimethylformamide (5.25 mL) in THF (5 mL), and stirring was continued for further 30 minutes. The reaction mixture was then poured into 2M aqueous KHCO3 (1.2 L), tert-butyl methyl ether (1.2 L) was added, and after stirring for 20 minutes, the layers were separated, the organic layer extracted twice with tert-butyl methyl ether (total volume 0.3 L). The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo to give N-(5-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (7 g) as an yellow oil that was used directly in the next step.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:9]([O-])(=O)/C=C/C.CC1CC1C([O-])=O>CS(C)=O>[CH3:4][CH:3]1[CH2:9][CH:2]1[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C/C=C/C(=O)[O-]
Reactant: C/C=C/C(=O)OCC
Agent: CC1CC1C(=O)[O-]
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1C
Temperature: 17.5 °C
Yield: 26.8 %

Procedure:
To a solution of ethyl trans-crotonate (1.20 kg, 1.31 L, 1.00 equivalent) in DMSO (3.00 L) at ambient temperature is added the above preformed ylide solution over 30 min, while the temperature of the reaction mixture is maintained at about 15-20° C. The progress of the reaction is followed by analysis by gas chromatography (GC, conditions below) until only a small amount of residual crotonate relative to the 2-methylcyclo-propanecarboxylate is observed (about 20-24 h). The reaction mixture is split into two equal (8.5 L) portions for work-up; each portion is treated as follows: Methyl t-butyl ether (MTBE, 6 L) is added, and the biphasic mixture is cooled to 15° C. before the dropwise addition of water (6 L) over about 45 min while maintaining the temperature below 23° C. After the phases are separated, the organic phase is washed twice with 10% brine; and the solvent is gently removed under vacuum (400 mbar, bath temperature 35° C.) to afford the ethyl 2-methylcyclopropanecarboxylate (1.00 kg, 26.8%) containing about 3.3 equivalents of MTBE.