Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][C:6]([NH:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:7][CH:8]=1.B(Br)(Br)Br.CO>ClCCCl>[OH:2][C:3]1[CH:4]=[N:5][C:6]([NH:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:7][CH:8]=1
Reactant: CCCCCC(=O)Nc1ncc(OC)cn1
Agent: BrB(Br)Br
Solvent: ClCCCl
Solvent: CO
Product: CCCCCC(=O)Nc1ncc(O)cn1
Yield: 58.1 %

Procedure:
N-(5-Methoxypyrimidin-2-yl)hexanamide (17.26 g, 77 mmol) was suspended in 1,2-dichloroethane (170 mL), the suspension was added with boron tribromide (20.5 mL, 216 mmol), and the mixture was refluxed by heating for 30 minutes. The reaction mixture was inactivated with methanol (170 mL) under ice cooling. The reaction mixture was concentrated under reduced pressure, the resulting residue was added with saturated ammonia in methanol (85 mL) under ice cooling, and the mixture was homogenized. The reaction mixture was concentrated under reduced pressure, and the resulting residue was added with water, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was isolated and purified by silica gel column chromatography (hexane:acetone=2:1) to obtain N-(5-hydroxypyrimidin-2-yl)hexanamide (9.36 g, 59%) as pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH3:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:10]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:1]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]#[N:7])[CH3:11]
Reactant: BrCCCCCBr
Reactant: CCc1cc(C#N)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1cc(C#N)ccc1N1CCCCC1
Temperature: 160 °C
Yield: 18.8 %

Procedure:
4-Amino-3-ethylbenzonitrile (3.0 g, 20.5 mmol), 1,5-dibromopentane (11.1 mL, 82.1 mmol), potassium carbonate (5.67 g, 41.0 mmol) and water (39.6 mL) were all split equally between ten microwave vials and each heated at 160° C. for 1 h. All reaction mixtures were combined and extracted twice with ethyl acetate (40 mL) and the combined organic fractions dried (phase separator) and concentrated in vacuo. Dichloromethane was added and then the mixture filtered before the filtrate was purified by silica chromatography, eluting 2-5% ethyl acetate in hexane to give the title compound as a colourless oil (823 mg, 3.85 mmol). Analysis indicated that the compound contained a small dibromopentane impurity. δH (methanol-d4, 400 MHz) 7.52 (1H, dd), 7.47 (1H, dd), 7.13 (1H, d), 2.89 (4H, dd), 2.71 (2H, q), 1.76-1.71 (4H, m), 1.64-1.56 (2H, m), 1.25 (3H, t). MS (ES): C14H18N2 requires 214; found 215 (MH+).
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:33]=[CH:32][C:8]2[O:9][C:10]3[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=3[CH2:12][N:13]([C:14](=[O:27])[CH2:15][N:16]3C(=O)C4C(=CC=CC=4)C3=O)[C:7]=2[CH:6]=1>C(O)C>[NH2:16][CH2:15][C:14]([N:13]1[CH2:12][C:11]2[CH:28]=[CH:29][CH:30]=[CH:31][C:10]=2[O:9][C:8]2[CH:32]=[CH:33][C:5]([Cl:4])=[CH:6][C:7]1=2)=[O:27]
Reactant: O=C1c2ccccc2C(=O)N1CC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
Hydrazine monohydrate (1.25 mi) and 8-chloro-10,11-dihydro-10[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)acetyl]-dibenz[b,f][1,4]-oxazepine (5.00 grams) were refluxed in absolute ethanol (125 mi) for 4 hours. The resulting mixture was filtered hot, and the collected solid was rinsed twice with ethanol, and then with hot methylene chloride. The filtrate and rinses were combined, evaporated i-n vacuo, and purified by flash chromatography through silica gel 60 (300 mi) using 95:5:0.5 chloroform:methanol:ammonium hydroxide. Trituration of the purified product with ethyl ether/hexane yielded the title compound as a white solid. Yield: 2.91 grams (84%). Mp: 108°-1090° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[Br:22]N1C(=O)CCC1=O>ClCCl>[Br:22][C:7]1[N:8]=[C:3]([CH2:1][CH3:2])[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Solvent: ClCCl
Product: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Temperature: 0 °C
Yield: 90.9 %

Procedure:
A solution of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol (1.94 g, 6.8 mmol) in dichloromethane (35 mL) was purged with nitrogen and cooled to 0° C. This light purple/grey homogenous solution was treated with a single portion of N-bromosuccinimide (1.34 g, 7.5 mmol) instantly becoming a lighter color. The reaction was warmed to room temperature for 15 minutes, transferred to a separatory funnel, diluted with 100 mL additional dichloromethane, washed twice with water (75 mL), and once with brine (75 mL). The organics were dried over MgSO4, filtered, and concentrated to give a golden oil. This material was purified by biotage MPLC (90 g column, 15% ethyl acetate/heptane) to afford 2.24 g (90%) of the title compound as a pale yellow solid. IR (diffuse reflectance) 3416, 3355, 2969, 2941, 1555, 1538, 1482, 1385, 1378, 1295, 1285, 1200, 1181, 1043, 733 cm−1; OAMS supporting ions at: ESI+ 361.9; MS (EI) m/z 361 (M+); [α]25D=−35 (c 0.53, methylene chloride); Anal. Calcd for C17H20BrN3O: C, 56.36; H, 5.56; N, 11.60. Found: C, 56.46; H, 5.59; N, 11.50.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[CH3:7][O:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[O:11][CH2:12][CH:13]1[NH:17][CH2:16][CH2:15][S:14]1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([N:17]1[CH2:16][CH2:15][S:14][CH:13]1[CH2:12][O:11][C:10]1[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=1[O:8][CH3:7])=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: COc1ccccc1OCC1NCCS1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1OCC1SCCN1C(=O)C(C)Br
Reaction time: 1 h

Procedure:
α-Bromopropionyl chloride (0.97 ml) in methylene chloride (15 ml) is added dropwise to a mixture of 2-(o-methoxyphenoxy)methyl-thiazolidine (2 g) and triethylamine (1.35 ml) in CH2Cl2 (30 ml) at 0°-5° C. After 1 hour, the mixture is washed with water and the usual work-up gives 3-α-bromopropionyl-2-(o-methoxyphenoxy)methyl-thiazolidine as a colourless oil.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:6][CH:5]=1.Cl[CH2:15][C:16]1[C:17]([CH3:25])=[C:18]([CH3:24])[CH:19]=[C:20]([CH3:23])[C:21]=1[CH3:22]>CCO.O>[CH3:22][C:21]1[C:20]([CH3:23])=[CH:19][C:18]([CH3:24])=[C:17]([CH3:25])[C:16]=1[CH2:15][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:8][CH:9]=1
Reactant: Cc1cc(C)c(C)c(CCl)c1C
Reactant: CCC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(=O)c1ccc(OCc2c(C)c(C)cc(C)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
NaOH (1.6 g, 40 mmol) is added to the solution of 1-(4-hydroxy-phenyl)-propan-1-one (3.0 g, 20 mmol) in EtOH (50 mL) and water (30 mL), followed by the addition of 3-Chloromethyl-1,2,4,5-tetramethyl-benzene (5.5 g, 30 mol). The resulting mixture is heated to turn into clear solution and stirred at room temperature overnight. The reaction is quenched by 1N HCl and extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water, brine, dried (MgSO4), concentrated and chromatographed to afford the titled compound as a white solid (4.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([O:8][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:7]=1
Reactant: COc1ccc(CBr)cc1
Reactant: Oc1cc(Br)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
To a solution of 5-bromo-2-chlorophenol (1.0 g) in tetrahydrofuran (10 ml) under nitrogen was added sodium hydride, 60% dispersion in mineral oil (0.20 g). The solution was stirred at room temperature. After 30 minutes a solution of 4-methoxybenzylbromide (0.97 g) was added in tetrahydrofuran (7 ml). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was partitioned between dichloromethane and brine, then dried (MgSO4), the solvents were removed in vacuo to give a crude residue. This crude residue was purified using flash chromatography to give 4-bromo-1-chloro-2-(4-methoxy-benzyloxy)-benzene (0.96 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][CH:6]([CH2:23][CH2:24][CH3:25])[C:7]([O:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:30]([C:34]1[N:35]=[C:36]([C:39]2[O:40][C:41]3[CH:47]=[CH:46][C:45](O)=[CH:44][C:42]=3[CH:43]=2)[S:37][CH:38]=1)([CH3:33])([CH3:32])[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:30]([C:34]1[N:35]=[C:36]([C:39]2[O:40][C:41]3[CH:47]=[CH:46][C:45]([O:1][CH2:2][C:3]4[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=4[O:5][CH:6]([CH2:23][CH2:24][CH3:25])[C:7]([O:9][CH:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[O:8])=[CH:44][C:42]=3[CH:43]=2)[S:37][CH:38]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1csc(-c2cc3cc(O)ccc3o2)n1
Reactant: CCCC(Oc1ccccc1CO)C(=O)OC(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a solution of diphenylmethyl 2-[2-(hydroxymethyl)phenoxy]pentanoate (1.70 g), 2-(4-tert-butylthiazol-2-yl)-5-hydroxybenzofuran (2.43 g), and triphenylphosphine (2.44 g) in tetrahydrofuran (40 ml) was added a solution of diethylazodicarboxylate (1.44 g) in tetrahydrofuran (2 ml) under ice-cooling. The mixture was stirred at the same temperature for an hour and at room temperature for an hour. The mixture was concentrated under reduced pressure and the residue was subjected to a column of silica gel (100 g) eluting with a mixed solvent of toluene and n-hexane (7:3) to give diphenylmethyl 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}pentanate (2.16 g).
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11].C[O:22][C:23]([C:25]1([CH2:39][O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:29][C:28](=[O:30])[N:27]([C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:26]1)=O.CC(O)=O>C1COCC1>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:9]=[C:10]([NH:11][C:23]([C:25]2([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:29][C:28](=[O:30])[N:27]([C:31]3[C:32]([CH3:38])=[CH:33][CH:34]=[CH:35][C:36]=3[CH3:37])[CH2:26]2)=[O:22])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: COC(=O)C1(COCc2ccccc2)CC(=O)N(c2c(C)cccc2C)C1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1CC(COCc2ccccc2)(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1=O
Temperature: 25 °C
Yield: 10 %

Procedure:
n-BuLi (2.8 M solution in hexanes, 183 μL, 0.513 mmol) was added to a cooled (−50° C.) solution of 3,5-bis-trifluoromethylaniline (84.5 μL, 0.545 mmol) in THF (3 mL). The resulting dark brown colored solution was slowly warmed to room temperature and stirred for an hour. A solution of 3-benzyloxymethyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step a, 100 mg, 0.27 mmol) in THF (2 mL) was added and the solution was stirred for 2 h at 70° C. The reaction mixture was then cooled to room temperature, AcOH (100 μL) was added and the solution was purified by automated flash chromatography (SiO2, 10→50% EtOAc/hexanes) followed by preparative HPLC (15→85% gradient of MeCN—H2O with 0.1% TFA). The pure fractions were lyophilized to afford 3-benzyloxymethyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid (3,5-bis-trifluoromethylphenyl)-amide (15 mg, 10% yield). LC-MS: Rt (retention time): 3.38 min, MS: (ES) m/z 565.2 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ 10.2 (s, 1H), 8.28 (s, 2H), 7.8 (s, 1H), 7.2-7.28 (m, 5H), 7.05-7.15 (m, 3H), 4.5-4.58 (m, 2H), 4.03 (d, 1H, J=8 Hz), 3.86-3.92 (m, 2H), 3.6 (d, 1H, J=8 Hz), 3.08 (d, 1H, J=16 Hz), 2.64 (d, 1H, J=16 Hz), 2.05 (s, 3H), 2.06 (s, 3H).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17][O:18][C:19]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=5)[N:22]=[CH:21][CH:20]=4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[O:39]1CCOCC1>>[CH3:30][O:29][C:25]1[CH:24]=[C:23]2[C:28]([C:19]([O:18][CH2:17][C:14]3[N:12]4[N:13]=[C:8]([C:5]5[CH:4]=[CH:3][C:2](=[O:39])[NH:7][CH:6]=5)[CH:9]=[CH:10][C:11]4=[N:16][N:15]=3)=[CH:20][CH:21]=[N:22]2)=[CH:27][CH:26]=1
Reactant: C1COCCO1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(F)nc5)nn34)ccnc2c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(=O)[nH]c5)nn34)ccnc2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
4-((6-(6-Fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.121 g, 0.30 mmol) was suspended in dioxane (1 mL) then added 3M aqueous hydrochloric acid (2.0 ml, 6.0 mmol). The reaction mixture was then heated at 100° C. for 1 hour. The mixture was concentrated under vacuum and the remaining solid was dissolved in methanol (4 mL) then added triethylamine (0.42 ml, 3.0 mmol). The mixture was stirred at room temperature for 1 hour then concentrated under vacuum. The sample was purified by flash chromatography eluting with 15% 7N NH3 in methanol/dichloromethane to afford 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2(1H)-one as a pale orange solid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:36]1[CH:41]2[CH2:42][NH:43][CH2:44][CH2:45][N:40]2[CH2:39][CH2:38][O:37]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:43]3[CH2:44][CH2:45][N:40]4[CH:41]([CH2:36][O:37][CH2:38][CH2:39]4)[CH2:42]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1CN2CCOCC2CN1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1ccccc1-c1cc(N2CCN3CCOCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 38.2 %

Procedure:
A solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2002/16324A1] (200 mg, 0.388 mmol), octahydropyrazino[2,1-c][1,4]oxazine (EP472826, 111 mg, 0.776 mmol), and potassium carbonate (161 mg, 1.165 mmol) in 1 mL of DMSO was heated to 150° C. for 47 h. It was worked up by diluting with dichloromethane and extracting with brine. The organics were dried (Na2SO4), and the solvent removed. The product was purified by flash chromatography: silica, dichloromethane to dichloromethane: MeOH 95:5. Obtained 92 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]([S:6][C:7]1([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:3](Cl)=[O:4].[CH3:14][N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[S:17][C:16]1=[N:23][OH:24].C(N(CC)CC)C>O1CCOCC1>[CH3:1][N:2]([S:6][C:7]1([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:3]([O:24][N:23]=[C:16]1[N:15]([CH3:14])[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[S:17]1)=[O:4]
Reactant: CN(SC1(C)CCCC1=O)C(=O)Cl
Reactant: CN1C(=O)C(C)(C)SC1=NO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(SC1(C)CCCC1=O)C(=O)ON=C1SC(C)(C)C(=O)N1C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 3.93g 0.0225m) of 3,5,5-trimethyl-2-oximino-thiazolidin-4-one and 2.28g (0.0225m) of triethylamine in 75 ml of dioxane was added dropwise with stirring 5.0g (0.0225m) of N-methyl-N-(2-methyl-1-oxo-2-cyclopentanesulfenyl)carbamoyl chloride whilst maintaining the temperature between 10°-15° C. The reaction mixture was left standing for 16 hours at 5° C, and then diluted with ice water. The product was extracted in ethylacetate, dried and concentrated to yield 0.66g of white solid, m.p. 119°-121° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:4]([CH2:25][CH3:26])[N:3]=1.OS(O)(=O)=O.C(OCC)(OCC)O[CH2:34][CH3:35].C([O-])([O-])=O.[K+].[K+]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][C:22]([O:24][CH2:34][CH3:35])=[O:23])=[C:4]([CH2:25][CH3:26])[N:3]=1
Reactant: CCc1nc(N)nc(N)c1OCCCOc1ccccc1CCC(=O)O
Reactant: CCOC(OCC)OCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCc1ccccc1OCCCOc1c(N)nc(N)nc1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 2,4-diamino-6-ethyl-5-(3-(2-(2-carboxyethyl)phenoxy)propoxy)pyrimidine (0.3604 g, 1 mmol) and a catalytic amount of con. H2SO4 in EtOH (4 mL) was added triethyl orthoformate (2 mL) and the mixture was left stirring at 25° C. for 8 hours. The reaction mixture was neutralized with K2CO3 and evaporated to dryness. The crude product was diluted with water and extracted with CH2Cl2. Evaporation to dryness gave the desired ester as white solid (0.3496 g, 90%, mp. 124.5-1255.5° C.). 1H NMR (500 MHz, DMSO-d6): 1.24 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.7 Hz), 2.26 (2H, m), 2.59 (2H, q, J=7.7 Hz), 2.62 (2H, t, J=7.7 Hz), 2.95 (2H, t, J=7.7 Hz), 3.98 (2H, t, J=6.0 Hz), 4.13 (2H, q, J=7.1 Hz), 4.27 (2H, t, J=5.7 Hz), 5.17 (2H, bs), 5.28 (2H, bs), 6.90 (1H, d, J=8.2 Hz), 6.93 (1H, t, J=7.5 Hz), 7.17 (1H, dd, J=7.4, 1.4 Hz), 7.22 (1H, dt, J=7.8, 1.5 Hz).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]I.[CH:12]#[CH:13]>>[CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:12]#[CH:13]
Reactant: COC(CCCCCI)OC
Reactant: C#C
Product: C#CCCCCCC(OC)OC
Yield: 96 %

Procedure:
Acetylene was bubbled through ca. 300 ml of liquid ammonia while 8.1 g (0.35 atom) of sodium was added in small pieces. After the disappearance of the blue color, dimethylsulfoxide (150 ml) was added cautiously. 1,1-Dimethoxy-6-iodohexane (8.16 g; 0.3 Mole) was then added over a period of 10 min. while acetylene was bubbled through the stirred mixture. The ammonia was allowed to evaporate and was replaced with ether. When the mixture had reached 0°, dilute NH4Cl solution was added. The organic layer was separated, washed with water, dried (Na2SO4), and evaporated. Distillation of the residue gave 48.9 g (96%) of 1,1-dimethoxy-oct-7-yne, b.p. 91°/8 Torr.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[CH3:29][C:30]1([CH3:38])[CH2:35][CH:34]([CH3:36])[CH2:33][CH:32](O)[CH2:31]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([O:19][CH:32]1[CH2:33][CH:34]([CH3:36])[CH2:35][C:30]([CH3:38])([CH3:29])[CH2:31]1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: CC1CC(O)CC(C)(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: CC1CC(OC(=O)[C@@H]2CCC(=O)N2C(=O)OCc2ccccc2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
34.2 g (0.13 mol) of N-benzyloxycarbonyl-L-pyroglutamic acid (prepared according to Berichte 97, 2434 [1964] or Annalen 649, 183 [1961]) are added to 150 ml of dimethylformamide, followed by 2 g of dimethylaminopyridine and then 18.48 g (0.13 mol) of 3,3,5-trimethylcyclohexanol (mixture of 90% trans isomer and 10% cis isomer) diluted in 50 ml of dimethylformamide. 26.8 g (0.13 mol) of dicyclohexylcarbodiimide are then run in over a period of about 15 minutes, the reaction medium being kept at +5° C. The mixture is then stirred at room temperature for 24 hours, after which the solvent is evaporated off, the residue is taken up with dilute hydrochloric acid and extraction is carried out with chloroform.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17]([OH:19])=[O:18])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26]O>C1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17]([O:19][CH3:26])=[O:18])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C(=O)O
Reactant: CO
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Product: COC(=O)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-carboxy-5-phenylisoxazole (0.2 g) was dissolved in a mixture of methanol and benzene (1:5, 10 ml), and trimethylsilyldiazomethane (0.6 ml, 2.0M hexane solution) was added dropwise thereto under ice-cooling, followed by stirring of the mixture at room temperature for 30 minutes. The reaction mixture was poured into an ice-cold water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to obtain the title compound (0.17 g, 81%) as a colorless solid.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][C:8]1[N:9]=[C:10]([C:17]#[N:18])[N:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=12.C(O)(=O)C.[Cl-].[NH4+:28]>CO>[F:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][C:8]1[N:9]=[C:10]([C:17](=[NH:28])[NH2:18])[N:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=12
Reactant: N#Cc1nc(Cc2ccccc2F)c2ncccn12
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1nc(Cc2ccccc2F)c2ncccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon atmosphere, 6.98 g (32.30 mmol) of sodium methylate (25% solution in methanol) was put in 50 ml methanol and 8.000 g (30.76 mmol) of 8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidine-6-carbonitrile dissolved in 40 ml of absolute methanol was added. The reaction mixture was stirred for 1 h at RT. 7.205 g (119.98 mmol) of acetic acid and 1.975 g (36.92 mmol) of ammonium chloride were added and the mixture was stirred for 2 h at 50° C. The reaction mixture was concentrated by evaporation and the residue was distributed between 150 ml water and 100 ml ethyl acetate. The aqueous phase was made basic (pH=10) with 2N sodium hydroxide solution and the phases were stirred for 1 h at RT. Water was added and it was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate, concentrated by evaporation and the residue was dried under high vacuum. 7.53 g (purity 73%, 66% of theor.) of the target compound was obtained.