Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(CC(O)=O)C.[C:7]([O:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:22]([NH:23][C:24](=[O:34])[C:25](=[N:32][OH:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21](=[O:35])[N:16]2[C:17]=1[C:18]([OH:20])=[O:19])(=[O:9])[CH3:8].[Cl:36][CH2:37][CH2:38][N:39]=[C:40]=[O:41].Cl.P([O-])([O-])([O-])=O>CN(C)C=O.C(N(CC)CC)C>[C:7]([O:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:22]([NH:23][C:24](=[O:34])[C:25](=[N:32][O:33][C:40](=[O:41])[NH:39][CH2:38][CH2:37][Cl:36])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21](=[O:35])[N:16]2[C:17]=1[C:18]([OH:20])=[O:19])(=[O:9])[CH3:8]
Reactant: O=C=NCCCl
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCCC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)NCCCl)c3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-acetoxymethyl -7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylic acid ethyl acetate solvate (syn-isomer) (1.0 g.) in dimethylformamide (21 ml.) containing triethylamine (0.425 g) was added 2-chloroethylisocyanate (0.274 g.) and the mixture was stirred at room temperature for one hour. The reaction mixture was acidified (2N hydrochloric acid) and extracted with ethyl acetate. The extracts were combined and extracted with saturated aqueous sodium bicarbonate. The combined aqueous extracts were acidified (2N-hydrochloric acid) and extracted with ethyl acetate, dried, concentrated and added dropwise to petroleum with vigorous stirring. The precipitated solid was filtered, dissolved in ethyl acetate (10 ml.) and added dropwise to petroleum (300 ml.). The precipitate was filtered and dried giving the title acid (0.76 g; 74%), [α]D + 28° (c 1.0 DMSO), λmax. (pH 6 phosphate buffer) 257.5 nm. (ε 20,780), νmax. (Nujol) 3270 (NH), 1780 (β-lactam), 1660 and 1520 cm.-1 (amide), τ (DMSO-d6) values include -0.10 (doublet, J 8 Hz; NH), 6.2-6.7 (multiplet; C-2 CH2 + -CH2CH2Cl), 7.95 (singlet; OCOCH3).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[O:48][CH3:49])=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>O>[CH:13]([O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[O:48][CH3:49])=[CH:21][CH:22]=1)([CH3:15])[CH3:14]
Reactant: CCCc1nc(OC)n(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(OC)n(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogen carbonate (1.9 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-isopropoxyphenyl)-2-methoxy-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.56 g) was added, and the mixture was stirred at 90° C. for 5 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.21 g, 33%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)/C=C/c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 13.6 %

Procedure:
tert-Butyl (E)-3-(2-cyano-4-pyridyl)acrylate (0.84 g, 3.2 mmol) and methyl thiosalicylate (0.74 g, 4.4 mmol) were dissolved in toluene (3 ml), and triethylamine (0.77 ml, 5.5 mmol) was added thereto. The reaction mixture was refluxed for 7 hrs and subjected to a silica gel (50 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated. The residue was recrystallized from ethyl acetate-isopropyl ether to give the titled compound (0.16 g, 17%) as white crystals.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[F:18][C:19]([F:57])([F:56])[C:20]1[CH:21]=[C:22]([CH2:30][O:31][C@@H:32]2[CH2:38][CH2:37][C@@H:36]3[N:39]([CH2:40][CH:41]=[CH2:42])[C@@:33]2([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:34][C@H:35]3[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>C1COCC1>[F:56][C:19]([F:18])([F:57])[C:20]1[CH:21]=[C:22]([CH2:30][O:31][CH:32]2[CH2:38][CH2:37][CH:36]3[N:39]([CH2:40][CH:41]=[CH2:42])[C:33]2([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:34][CH:35]3[C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1
Reactant: C=CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)C[C@H]2C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCN1C2CCC(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C1(c1ccccc1)CC2C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of potassium bis(trimethylsilyl)amide in toluene (0.5M, 1.5 ml, 0.75 mmol) was added to a stirred solution of (1R*,2R*,5S*,6R*)-2-{[3,5-bis(trifluoromethyl)-phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1]octane (Example 80; 362 mg, 0.635 mmol) in THF (5 ml) at +5° C. The mixture was stirred for 15 minutes and quenched with saturated aqueous NH4Cl and extracted into diethyl ether. The organic extracts was washed with water, dried (Na2SO4) and concentrated to give the title compound as a 4.6:1 mixture diastereoisomers.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[C:12]1([C:18]#[C:19][C:20](O)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:20](=[O:21])[C:19]#[C:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)C#Cc1ccccc1
Agent: Cl
Product: O=C(C#Cc1ccccc1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and 3-phenylpropynoic acid; MS (ES+) 255 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[Br:21][C:22]1[CH:23]=[C:24]2[CH2:30][C:29](=[O:31])[NH:28][C:25]2=[N:26][CH:27]=1>>[Br:21][C:22]1[CH:23]=[C:24]2[C:30](=[CH:19][C:3]3[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[C:7](=[O:18])[C:6]=4[C:2]=3[CH3:1])[C:29](=[O:31])[NH:28][C:25]2=[N:26][CH:27]=1
Reactant: O=C1Cc2cc(Br)cnc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3ncc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 37 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as starting materials to give 2-(5-bromo-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (35 mg, 37.0%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18](=[O:20])[CH3:19])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: ClCc1ccc(Cl)cc1
Product: CC(=O)Cc1ccc(OCc2ccc(Cl)cc2)cc1

Procedure:
Prepared from 4-chlorobenzyl chloride and 4-hydroxyphenyl acetone by the method of Example 2 (b).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:10]=1[CH3:11])(=[O:5])[CH3:4].O.Cl>C(O)C>[CH3:11][C:10]1[O:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7][C:6]=1[CH:3]([OH:5])[CH3:4]
Reactant: CC(=O)c1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1C(C)O
Reaction time: 1 h
Yield: 85.8 %

Procedure:
Sodium borohydride (1.41 g) was added portionwise, at 0° C., to a solution of 4-acetyl-5-methyl-2-phenyloxazole (15.0 g) in ethanol (100 ml). The mixture was stirred for 1 hour at the same temperature, and then for 1 hour at room temperature. The reaction mixture was poured into water, which was neutralized with 2N HCl to obtain 1-(5-methyl-2-phenyl-4-oxazolyl)ethanol (13.0 g, 86%), which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.101-102° C.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[O:41])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccnc4)c3C2=O)C(=O)N1
Yield: 64.7 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.98 g, 6.48 mmol) was added to stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, nicotinoyl chloride (0.41 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (SiO2, CH2Cl2:CH3OH 97.5:2.5) to give N-{[(2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-3-pyridylcarboxamide (0.47 g, 64%) as a white solid: mp 148–151° C.; 1H NMR (DMSO-d6) δ d 11.16 (s, 1H), 9.36 (t, J=5.6 Hz, 1H), 9.09 (d, J=1.25 Hz, 1H), 8.75–8.73 (m, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.84–7.76 (m, 3H), 7.57–7.52 (m, 1H), 5.22–5.15 (dd, J=5.4 and 12.7 Hz, 1H), 4.96 (d, J=5.6 Hz, 2H), 2.92–2.85 (m, 1H), 2.65–2.50 (m, 2H), 2.11–2.06 (m, 1H); 13C NMR (DMSO-d6) δ d 172.72, 169.80, 167.51, 166.94, 165.23, 152.02, 148.44, 138.86, 135.10, 134.83, 133.20, 131.55, 129.48, 127.20, 123.49, 121.95, 48.89, 38.33, 30.93, 21.98; Anal. Calcd. For C20H16N4O5+0.28 H2O: C, 60.45; H, 4.20; N, 14.10. Found: C, 60.29; H, 4.28; N, 13.82.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28]([CH:30]2[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]2)=O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:18]=[C:28]([CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)[C:30]3[CH2:31][O:32][CH2:33][CH2:34][C:35]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: COc1cccc(CC(=O)C2COCCC2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COc1cccc(Cc2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc3c2COCC3)c1
Yield: 6.2 %

Procedure:
1-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (85 mg, 0.35 mmol), 3-(2-(3-methoxyphenyl)acetyl)dihydro-2H-pyran-4(3H)-one (86 mg, 0.35 mmol) and potassium carbonate (47.9 mg, 0.35 mmol) in ethanol (2 mL) were heated to 60° C. over night. DCM and water were added and the organic phase was separated and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC yielding N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-(3-methoxybenzyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine (10.00 mg, 6%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]([NH2:21])=[CH:10][C:11]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]#[C:23]Br>CO.C(#N)C.O>[CH:1]1([N:7]2[C:8]3[CH:13]=[CH:12][C:11]([CH2:14][N:15]4[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:10][C:9]=3[N:21]=[C:23]2[NH2:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#CBr
Reactant: Nc1cc(CN2CCCCC2)ccc1NC1CCCCC1
Solvent: CO
Solvent: CC#N
Solvent: O
Product: Nc1nc2cc(CN3CCCCC3)ccc2n1C1CCCCC1
Reaction time: 4.5 h

Procedure:
N1-cyclohexyl-4-(piperidin-1-ylmethyl)benzene-1,2-diamine from step3 in methanol (200 mL) was added to a mixture of 5 M cyanogen bromide in acetonitrile (3.2 mL) and water (100 mL) dropwise over 1 hr with stirring. After 4.5 hr total reaction time, the mixture was evaporated to dryness. The residue was purified by preparative HPLC chromatography to yield 2.23 g of the title compound as the bis-TFA salt.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]2[CH2:13][C:14](=[O:16])[CH2:15][CH:10]2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:9]1[CH:10]2[CH2:15][C:14](=[O:16])[CH2:13][CH:11]2[CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC2CNCC2C1

Procedure:
reacting starting material 5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (I-1a) with trifluoroacetic acid in the solvent of dichloromethane in an ice-water bath to obtain hexahydro-cyclopenta[c]pyrrol-5-one triflutate (I-1b);
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:8]([O:10][C:11](=[O:33])[CH:12]([O:30][CH2:31][CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:16][CH:15]=1)[CH3:9].CCCCCCC>C1(C)C=CC=CC=1>[CH2:8]([O:10][C:11](=[O:33])[CH:12]([O:30][CH2:31][CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:27][CH:28]=2)=[CH:16][CH:15]=1)[CH3:9]
Reactant: CC(C)(C)N=C=O
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(O)cc2)cc1)OCC
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OC(=O)NC(C)(C)C)cc2)cc1)OCC
Yield: 20.3 %

Procedure:
tert-Butyl isocyanate (0.14 g; 1.4 mmole) was slowly added to a solution of 2-ethoxy-3-{4-[2-(4-hydroxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 26b) (0.5 g; 1.4 mmole) in toluene (5 ml) and thereafter the reaction mixture was stirred over night. The crude mixture was purified by chromatography on silica gel using ethyl acetate:heptane (gradient 1.25-80% ethyl acetate) as eluant to give 0.13 g (yield 20%) of 3-{4-[2-(4-tert-butylcarbamoyloxyphenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:4][Si:3]([CH2:2][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)([CH3:6])[CH3:5]
Reactant: O=Cc1ccc(O)cc1
Reactant: C[Si](C)(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)COc1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
Chloromethyltrimethylsilane (110.5 g, 0.9 mol) is added dropwise over 30 minutes to a mixture of para-hydroxybenzaldehyde (110 g, 0.82 mol) and potassium carbonate (124.5 g, 0.9 mol) in 1 L of dry DMF maintained at 80° C., and while sparging with nitrogen. The mixture is left at 90° C. for 4 hours. The reaction mixture is filtered and the solvent is removed from the filtrate by distillation under vacuum. The final traces of DMF are removed via a stage at 60° C. under a vacuum of 2 mmHg. 142.4 g (yield: 84%) of 4-trimethylsilanylmethoxybenzaldehyde are obtained in the form of an orange-yellow oil, which is used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH3:16])[C:13]([CH2:17][CH2:18][CH2:19][OH:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:26]([N:28]=C=O)=[O:27].C(N(CC)CC)C>O1CCCC1.O>[C:26]([O:20][CH2:19][CH2:18][CH2:17][C:13]1[N:14]([CH2:15][CH3:16])[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:21]([CH3:22])[CH3:23])[N:12]=1)(=[O:27])[NH2:28]
Reactant: CCn1c(CCCO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCn1c(CCCOC(N)=O)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
In 7 ml of dry tetrahydrofuran was dissolved 700 mg (1.9 mmol) of the alcohol (137b), and after the solution was cooled to -40° C., 530 mg (2.8 mmol) of trichloroacetyl isocyanate was added, the temperature was elevated to room temperature. After 30 minutes, 2 ml of water and 1 ml of triethylamine were added and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water and extracted with ethyl acetate and the extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% methanol-ethyl acetate) and recrystallized from ethyl acetate-n-hexane to provide 705 mg (yield 90%) of Compound I-149 as crystals. mp 128-129° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:14]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(O)c(C(F)(F)F)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Yield: 75.8 %

Procedure:
A solution of 4-hydroxy-3-(trifluoromethyl)benzaldehyde (1.5 g, 8.0 mmol), benzyl bromide (1.51 g, 8.8 mmol) and potassium carbonate (1.66 g, 12.0 mmol) in dimethyl formamide (20 mL) was stirred water (100 mL) and extracted 3 times with ethyl acetate. The ethyl acetate extracts were combined and washed 2 times with water and dried over magnesium sulfate. Concentration in vacuo yielded 1.7 g of 4-benzyloxy-3-trifluoromethyl-benzaldehyde which was used as such in the next step.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:18]([CH3:20])[CH3:19])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:17])OC1C=CC=CC=1)#[N:2].[CH3:21][N:22](C)[CH:23]=O>>[CH3:21][N:22]([CH3:23])[C:9]([NH:8][C:7]1[S:6][N:5]=[C:4]([N:18]([CH3:20])[CH3:19])[C:3]=1[C:1]#[N:2])=[O:17]
Reactant: CN(C)c1nsc(NC(=O)Oc2ccccc2)c1C#N
Reactant: CN(C)C=O
Product: CN(C)C(=O)Nc1snc(N(C)C)c1C#N

Procedure:
In a pressure bottle were placed 6.1 g of phenyl (4-cyano-3-(dimethylamino)-5-isothiazolyl)carbamate and 25 ml of dimethylformamide. This solution was cooled to 0°, and 2.8 ml (1.9 g) of dimethylamine (previously collected in a graduated dropping funnel using a dry-ice trap) were added. The reaction mixture was heated at 80° for 4 hours, cooled to -10° and the bottle was opened. The reaction mixture was concentrated to dryness under vacuum to give a tan solid. Recrystallization of the tan solid from ethanol gave 4.0 g of 1,1-dimethyl-3-(4-cyano-3-(dimethylamino)-5-isothiazolyl)urea, m.p. 203°-204°. A second crop was collected and was recrystallized from ethanol to give 0.2 g of needles; m.p. 201°-202°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: C[Al](C)C.[CH3:5]CCCCC.CNCCNC.[C:17]([C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:28]=1)[C:22]([O:24]C)=O)#[N:18]>C1(C)C=CC=CC=1.O>[C:22]([C:21]1[CH:20]=[C:19]([CH:28]=[C:27]([O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:26]=1)[C:17]#[N:18])(=[O:24])[CH3:5]
Reactant: COCCOc1cc(C#N)cc(C(=O)OC)c1
Reactant: CCCCCC
Agent: CNCCNC
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: COCCOc1cc(C#N)cc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
Solution of AlMe3 in hexane (19 mmol) was dropped to the solution of DMEDA (24 mmol) in 60 ml dry toluene slowly at 0° C. under N2. The solution was then continued to stir at room temperature for another 1 h and added methyl 3-cyano-5-(2-methoxyethoxy)benzoate (17.3 mmol) and stirred at reflux for 8 h. The mixture was poured to the water and extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, and concentrated to give 3-acetyl-5-(2-methoxyethoxy)benzonitrile (58.6%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[CH3:22][NH:23][CH3:24]>C1COCC1.ClCCl>[CH3:22][N:23]([CH3:24])[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4]
Reactant: CNC
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36 %

Procedure:
To a solution of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (67 mg, 0.225 mmol) in THF (3 mL), a 2 M solution of dimethylamine in THF (0.562 mL, 1.152 mmol) was added and the reaction mixture was stirred at room temperature for 48 hrs. The reaction mixture was diluted with dichloromethane (DCM, 5 mL) and solvents evaporated to afford N2,N2-dimethyl-N1-(3-quinoxalin-2-ylphenyl)glycinamide (25 mg, 36% yield). LCMS calculated for C18H18N4O (M+H): 307.37. found 307.20. 1H-NMR (MeOD, 400 Mhz) δH: 9.50 (1H, s), 8.65 (m, 1H), 8.30-8.15 (m, 3H), 8.00-7.87 (m, 3H), 7.60-7.55 (m, 1H), 4.30 (s, 2H), 3.15 (s, 6H).