Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]C>C1(C)C=CC=CC=1.C([Sn](=O)CCCC)CCC>[C:1]([C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])=[O:16])[CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1cc(C)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C)c(O)c(C(C)(C)C)c1
Yield: 99.5 %

Procedure:
Methyl 3-(3-tert-butyl-5-methyl-4-hydroxyphenyl)propionate (70.0 g), octadecyl alcohol (76.3 g) and dibutyltin oxide (0.74 g) were dissolved in toluene (70 ml), after which the mixture was heated, and the solvent (200 ml) was distilled off while adding toluene. The toluene was distilled off from the reaction mixture and the residue was purified by column chromatography to give octadecyl 3-(3-tert-butyl-5-methyl-4-hydroxyphenyl)propionate (136.0 g), m.p. 58°-59° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4](Cl)=[O:5].[C:8]([C:11]1[CH:30]=[CH:29][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:24]([CH3:28])=[CH:25][C:26]=2[Br:27])[NH2:23])=[C:13]([CH2:31][CH2:32][CH3:33])[C:12]=1[OH:34])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:7])[C:4]([NH:23][C:22]1[C:24]([CH3:28])=[CH:25][C:26]([Br:27])=[C:20]([O:19][CH2:18][CH2:17][CH2:16][O:15][C:14]2[CH:29]=[CH:30][C:11]([C:8](=[O:10])[CH3:9])=[C:12]([OH:34])[C:13]=2[CH2:31][CH2:32][CH3:33])[CH:21]=1)=[O:5]
Reactant: CCCc1c(OCCCOc2cc(N)c(C)cc2Br)ccc(C(C)=O)c1O
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(OCCCOc2cc(NC(=O)C(=O)OC)c(C)cc2Br)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In the course of approximately 5 minutes a solution of 3.2 ml of chloro-oxalic acid methyl ester in 10 ml of methylene chloride is added dropwise to a solution, cooled to 0°, of 14.0 g (32 mmol) of 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-bromo-6-methylaniline and 4.9 ml of triethylamine in 140 ml of methylene chloride and the whole is then stirred at room temperature for a further 90 minutes. The reaction mixture is poured onto ice-water and the organic phase is separated off, washed with water, dried over sodium sulphate and concentrated under reduced pressure. Crystallisation from ethyl acetate/ether/petroleum ether yields N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-bromo-6-methylphenyl}-oxamic acid methyl ester having a melting point of 92°-93°.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C1C(=O)N([Br:20])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N.O>ClC1C=CC=CC=1>[Br:20][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([CH3:12])[C:2]=1[OH:1]
Reactant: Cc1nc2ccccc2cc1O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Solvent: O
Product: Cc1nc2ccccc2c(Br)c1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
3-Hydroxy-2-methyl-quinoline (76 mg) was dissolved in chlorobenzene (7 ml) to prepare a solution. N-Bromosuccimide (180 mg) and 2,2′-azobisisobutyronitrile (23 mg) were added to the solution, and the mixture was stirred at 80° C. for one hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give 4-bromo-3-hydroxy-2-methyl-quinoline (35 mg, yield 31%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.BrC1C=NC=C([C:31]([F:34])([F:33])[F:32])C=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:31]([F:34])([F:33])[F:32])[CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Reactant: FC(F)(F)c1cncc(Br)c1
Product: Cc1ccc(Nc2cncc(C(F)(F)F)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 3-Bromo-5-(trifluoromethyl)pyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as an off-white solid, MS (ISP): m/e=377.4 (M+H+).
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:16](=[O:19])([O-])O.[Na+]>>[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([N:3]3[CH2:2][CH2:11][CH2:6][CH:16]([OH:19])[CH2:4]3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: O=S(=O)(c1cccc2cnccc12)N1CCCC(O)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In 100 ml of ice water was dissolved 10.6 g of 5-isoquinolinesulfonyl chloride hydrochloride, and the pH of the solution was adjusted to 6 with a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with of 200 ml of dichloromethane. The dichloromethane layer was added dropwise to a 100 ml of dichloromethane solution containing 6.0 g of 3-hydroxypiperidine and 6.0 g of triethylamine over 30 minutes while cooling with ice. The mixture was stirred at a temperature of 15° C. to 20° C. for 3 hours, washed with water, and dried with anhydrous magnesium sulfate. Then, the dichloromethane was removed under reduced pressure to obtain 8.50 g of 1-(5-isoquinolinesulfonyl)-3-hydroxypiperidine.
Reaction SMILES: [C:1](OC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C2CC(COC)OC=2C=1)=O)(C)(C)C.[C:31]([O:35][C:36]([C:38]1[CH:49]=[C:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([C:57]([N:59]3[CH2:62][CH2:61][CH2:60]3)=[O:58])=[C:53]([F:63])[CH:52]=2)[C:41]2[CH2:42][C:43]([CH2:46][OH:47])([CH3:45])[O:44][C:40]=2[CH:39]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32].CI>>[C:31]([O:35][C:36]([C:38]1[CH:49]=[C:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([C:57]([N:59]3[CH2:62][CH2:61][CH2:60]3)=[O:58])=[C:53]([F:63])[CH:52]=2)[C:41]2[CH2:42][C:43]([CH2:46][O:47][CH3:1])([CH3:45])[O:44][C:40]=2[CH:39]=1)=[O:37])([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)c(F)c2)c2c(c1)OC(C)(CO)C2
Reactant: COCC1Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)OC(C)(C)C)cc2O1
Solvent: CI
Product: COCC1(C)Cc2c(Oc3ccc(C(=O)N4CCC4)c(F)c3)cc(C(=O)OC(C)(C)C)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 201a, from 4-[4-(azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (240a) and methyl iodide. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.84 Hz, 2 H) 7.22 (s, 1 H) 7.07 (d, J=8.84 Hz, 2 H) 3.41-3.52 (m, 2 H) 3.40 (s, 3 H) 3.11 (d, J=16.67 Hz, 1 H) 2.76 (d, J=16.67 Hz, 1 H) 2.48 (td, J=7.89, 4.67 Hz, 1 H) 1.56 (s, 9 H) 1.46 (s, 3 H) 1.32-1.43 (m, 2 H) 1.00-1.12 (m, 2 H); LCMS for C26H30FNO6 m/z 472.20 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[NH:11][C:10](=[O:15])[N:9]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[N:18]=[C:8]3[C:7]=2[CH2:6]1.[H-].[Na+].[C:32](Cl)(=[O:34])[CH3:33]>CN(C=O)C.C(OCC)(=O)C>[C:32]([N:11]1[C:12]2[CH2:13][CH2:14][N:5]([CH2:4][C:3]3[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=3[F:1])[CH2:6][C:7]=2[C:8]2=[N:18][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[CH:16][N:9]2[C:10]1=[O:15])(=[O:34])[CH3:33]
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CN(Cc1ccccc1F)CC2
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)n1c2c(c3nc(-c4ccccc4F)cn3c1=O)CN(Cc1ccccc1F)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 9-(2-fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (392 mg, 1 mmol) and 50% sodium hydride(144 mg, 3 mmol) in DMF (5 mL) was stirred at room temperature for 15 min. Acetyl chloride (1 mL) was added and stirring was continued for 30 min. The reaction was diluted with ethyl acetate and washed with water. After drying over magnesium sulfate, the solvent was removed in vacuo and the residue was subjected to flash chromatography on silica gel with 30% ethyl acetate in hexane as the eluent to afford 6-acetyl-9-(2-fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (compound 55) and 5-acetoxy-9-(2-fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2c]pyrido[3,4-e] pyrimidine (compound 56) as white solids.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:1][C:2]2[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=2[CH3:10])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(O)c(=O)ccn1C
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2c(C)n(C)ccc2=O)cc1
Yield: 86 %

Procedure:
3-Hydroxy-1,2-dimethylpyridin-4(1H)-one (0.2 g, 1.4 mmol) was reacted with p-toluenesulfonyl chloride (0.82 g, 4.3 mmol) in 10 mL of pyridine to afford PZBG-3b in 86% yield (0.35 g, 1.2 mmol). 1H NMR (500 MHz, CDCl3) δ=7.99 (d, J=8.4 Hz, 2H), 7.40 (d, J=7.6 Hz, 1H), 7.33 (d, J=8 Hz, 2H), 6.40 (d, J=7.2 Hz, 1H), 3.64 (s, 3H), 2.42 (s, 3H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3) δ=170.71, 145.67, 145.54, 141.48, 134.07, 129.72, 128.96, 126.07, 117.53, 42.25, 22.00, 14.7. ESI-MS(+): m/z 294.05 [M+H]+, 315.97 [M+Na]+.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH2:2][C:3]#[CH:4].I[C:19]1[C:27]2[O:26][CH2:25][C:24](=[O:28])[C:23]=2[CH:22]=[CH:21][C:20]=1[O:29][CH3:30]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:30][O:29][C:20]1[CH:21]=[CH:22][C:23]2[C:24](=[O:28])[CH2:25][O:26][C:27]=2[C:19]=1[C:4]#[C:3][CH2:2][CH2:1][CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1
Reactant: C#CCCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc2c(c1I)OCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1C#CCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 50 °C
Reaction time: 6 h
Yield: 54.2 %

Procedure:
A solution of tert-butyl 4-(but-3-ynyl)piperidine-1-carboxylate (0.370 g, 1.56 mmol) in triethylamine (10 mL) was added with 7-iodo-6-methoxybenzofuran-3(2H)-one (0.452 g, 1.56 mmol) synthesized in Example B46, Step 2, dichlorobis(triphenylphosphine)palladium(II) (0.110 g, 0.156 mmol) and copper(I) iodide (0.0297 g, 0.156 mmol), and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-ynyl]piperidine-1-carboxylate (0.338 g, 54%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:32]1[C:44]2[CH:43]([CH2:45][CH2:46][OH:47])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][CH:33]=1.[CH2:48]([O:50][CH:51]([CH2:57][C:58]1[CH:63]=[CH:62][C:61](O)=[CH:60][CH:59]=1)[C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH3:49]>C1COCC1.O>[CH2:48]([O:50][CH:51]([CH2:57][C:58]1[CH:59]=[CH:60][C:61]([O:47][CH2:46][CH2:45][CH:43]2[C:44]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[C:37]3[C:42]2=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:62][CH:63]=1)[C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH3:49]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: OCCC1c2ccccc2-c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCC2c3ccccc3-c3ccccc32)cc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Diethyl azodicarboxylate (0.235 ml, 1.49 mmol) was added at 0° C. to a stirred solution of triphenylphosphine (0.392 g, 1.49 mmol) and 2-(9H-fluoren-9-yl)-ethanol (0.208 g, 1.0 mmol) in dry THF (5 ml) and the mixture stirred for 5 min. A solution of ethyl 2-ethoxy-3-(4-hydroxy-phenyl)-propionate (0.356 g, 1.49 mmol) in dry THF (5 ml) was then added, the mixture allowed to warm to room temperature and stirring continued for 20 h. The resulting mixture was treated with water (50 ml), and the products extracted into dichloromethane (4×50 ml). The extracts were combined, washed with brine, dried (Na2SO4) and evaporated to a colourless gum. This was then purified by column chromatography on SiO2 (15% Et2O in petroleum eluent) to give the title compound as a colourless gum; 0.20 g (47%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11]>CO>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:10]([CH3:9])(=[O:12])=[O:11])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(O)cc1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
To a cold suspension of 4-aminophenol (5.45 g, 49.9 mmol) in MeOH (62 ml), methanesulfonyl chloride (1.95 ml, 25.2 mmol) was added under stirring maintaining the temperature between 10 and 15° C. The resulting solution was allowed to warm to RT and stirred for 2 hours. The solvent was removed under vacuum, and the residue was suspended in HCl 1N (62 ml); the insoluble was collected by filtration, washed with water, dried and purified by filtration through a silica gel pad (DCM:MeOH=100:15) affording N-(4-hydroxyphenyl)methanesulfonamide as a brown solid (1.35 g, 7.21 mmol, 28.6% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.CC1(C)CC(C)OB([C:31](=[CH2:36])[C:32]([F:35])([F:34])[F:33])O1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:21]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:31](=[CH2:36])[C:32]([F:35])([F:34])[F:33])=[N:3][N:4]=[CH:5]2
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
Reactant: C=C(B1OC(C)CC(C)(C)O1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(c1nncc2cc(-c3cc(C(=O)OC)ccc3C)ccc12)C(F)(F)F
Temperature: 100 °C
Yield: 69.9 %

Procedure:
A mixture of methyl 3-(1-chlorophthalazin-6-yl)-4-methylbenzoate (1.0 g, 3.2 mmol), 4,4,6-trimethyl-2-(1,1,1-trifluoroprop-2-en-2-yl)-1,3,2-dioxaborinane (0.99 g, 4.48 mmol), tetrakis(triphenylphosphine)palladium (185 mg, 0.16 mmol), and sodium carbonate monohydrate (1.2 g, 9.59 mmol) in dioxane/H2O (3:1, 12 mL) was heated in a microwave reactor at 100° C. for 80 min. The reaction mixture was partitioned between EtOAc (30 mL) and H2O (30 mL); the layers were separated, and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting dark oil was dissolved in 2% Et3N in EtOAc, evaporated onto some silica gel, and purified by flash chromatography (Biotage Si 40+S, 20-60% of 2% Et3N in EtOAc/hexanes) to provide methyl 4-methyl-3-(1-(1,1,1-trifluoroprop-2-en-2-yl)phthalazin-6-yl)benzoate (833 mg, 70% yield) as a brown solid. MS (ESI, pos. ion) m/z: 373.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@@H:4]([CH:5]=O)[C@@H:3]1[C:7]([O:9][CH3:10])=[O:8].[C:12](O)(=O)[CH2:13][C:14]([OH:16])=[O:15].CCCCCC>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:11])[C@@H:4](/[CH:5]=[C:13](/[C:14]([OH:16])=[O:15])\[CH3:12])[C@@H:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C(O)CC(=O)O
Reactant: COC(=O)[C@H]1[C@H](C=O)C1(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)[C@H]1[C@H](/C=C(\C)C(=O)O)C1(C)C
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 0.666 g of methyl (±)-trans-2,2-dimethyl-3-formylcyclopropanecarboxylate was dissolved in 10 mL of a designated solvent. A designated amount of an amine and 1.000 g of malonic acid was then added thereto, and the resulting mixture was stirred under heating. After the mixture was allowed to cool to room temperature, 50 mL of ethyl acetate was added to said mixture and the resulting mixture was washed with 3N-hydrochloric acid and then saturated brine to obtain an organic layer therefrom. The organic layer was dried over anhydrous magnesium sulfate and thereafter evaporated under reduced pressure in order to produce a residue. The residue was subjected to silica gel chromatography, wherein the eluent was a mixture of n-hexane and ethyl acetate at a volume to volume ratio of 3:1. Methyl(±)-trans-2,2-dimethyl-3-{2-carboxy-(E)-1-propenyl}cyclopropanecarboxylate was obtained.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][C:5]2=[O:15].[N+]([O-])([O-])=O.[Na+].[ClH:21]>O.[Cu]Cl>[Cl:21][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][C:5]2=[O:15]
Reactant: Cl
Reactant: Nc1ccc2c(c1)C(=O)CC21CCCC1
Agent: Cl[Cu]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CC2(CCCC2)c2ccc(Cl)cc21
Temperature: 100 °C

Procedure:
A mixture of 5'-amino-spiro(cyclopentane-1,1'-indan)-3'-one (20.1 g; 0.1 mole), 23% hydrochloric acid (35 ml), water (76 ml) and ice (3 g) is diazotised at about +5° C. with a solution of sodium nitrate (11 g) in water (25 ml). The clear solution is added to an ice cooled solution of copper(I)chloride(15 g) in 23% hydrochloric acid (150 ml) and water (60 ml). After agitation for 2.5 hours the mixture is heated to 100° C. for a short while and is then allowed to cool. The brown precipitate is sucked off and thoroughly washed with water. Crude yield 20 g (90%). The crude product is purified by distillation in vacuum, bp. 135°-136° C./1,5 mm Hg. A sample is crystallized from n-hexane and then melts at 54° C. The oxime melts at 140° C.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:9](Br)[CH3:10].C[O-].[Na+]>CO>[C:3]([CH:2]([CH2:9][CH3:10])[C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH3:5]
Reactant: CCBr
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(C(C)=O)C(=O)OC
Yield: 56.8 %

Procedure:
465 g of methyl acetoacetate and then 458 g of ethyl bromide were added under nitrogen to 720 g of 30% sodium methylate solution in 1200 ml of methanol. The reaction mixture was subsequently boiled at reflux. After distillation of the methanol the residue was poured on to ice-water. It was then extracted with n-hexane and water. The organic phases were combined and dried. After evaporation of the solvent and distillation there were obtained 328 g (56.9%) of methyl 2-acetylbutyrate, b.p. 77°-79°/15 Torr.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>>[CH3:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:14][CH:12]=[N:1]2
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: NC=O
Product: Cc1cccc2nc[nH]c(=O)c12
Temperature: 180 °C
Yield: 73 %

Procedure:
A mixture of 2-amino-6-methylbenzoic acid (5 g, 33 mmol) and formamide (15 ml) was heated in a microwave oven reactor at 180° C. for 30 min. After cooling to room temperature, the solid was collected by filtration, washed with water and dried under vacuum to give 1A (3.89 g, 73%) as a solid. The compound has an analytical HPLC retention time=1.019 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=161+.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[O:6]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[O:6]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][S:1](=[O:4])(=[O:3])[NH2:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NS(=O)(=O)Cl
Reactant: OCCCCOc1ccccc1
Product: NS(=O)(=O)OCCCCOc1ccccc1
Yield: 54 %

Procedure:
The title compound was prepared by procedures of Example 16 from sulfamoyl chloride and 4-phenoxy-1-butanol in 54% yield as an off-white solid, mp 76°-77° C.
Reaction SMILES: I[CH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[CH:12]=3)([CH2:7][CH2:8]1)[O:5][CH2:4]2.[C-:24]#[N:25].[Na+]>CN(C=O)C.CCOC(C)=O>[O:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[O:17][C:13]1[CH:12]=[C:11]([C:6]23[CH2:9][CH2:10][C:3]([CH2:2][C:24]#[N:25])([CH2:8][CH2:7]2)[CH2:4][O:5]3)[CH:16]=[CH:15][CH:14]=1
Reactant: [C-]#N
Reactant: ICC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 80 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of 4-(iodomethyl)-1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octane (1.5 g, 3.50 mmol) and NaCN (0.687 g, 14.01 mmol) in DMF (8 mL) was stirred at 80° C. for 18 h. The reaction was diluted with EtOAc (10 mL), washed with water (3×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give 2-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetonitrile (1.15 g, 3.50 mmol, 100% yield) as light brown oil. The above nitrile (1.15 g, 3.50 mmol) was taken up in ethylene glycol (20 mL) and treated with 40% KOH (5.00 mL, 35.0 mmol). The reaction was stirred at 165° C. for 18 h and concentrated in vacuo. The residue was dissolved in water (15 mL), acidified to pH 2 with 1 N aqueous HCl, and extracted with EtOAc (5×5 mL). The combined extracts were washed with brine, dried with MgSO4, filtered, and concentrated in vacuo to afford the title compound (0.91 g, 99% yield) as a light brown solid. LCMS, [M−H]+=261.3.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:24][CH:23]=2)[C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16]C)=[O:15])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([CH2:6][CH2:7][C:8]([N:10]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:26][CH:27]=2)[C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([OH:16])=[O:15])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCCCCCC#Cc1ccc(CN(C(=O)CCC2CCCC2)c2cccc(C(=O)OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC#Cc1ccc(CN(C(=O)CCC2CCCC2)c2cccc(C(=O)O)c2)cc1

Procedure:
The titled compound was prepared following the procedure F using methyl 3-[(3-cyclopentylpropanoyl)(4-dec-1-yn-1-ylbenzyl)amino]benzoate and NaOH 5N aq in the presence of MeOH as a pale yellow oil (86%). 1H NMR (CDCl3, 300 MHz) δ 8.07 (d, J=7.5 Hz, 1H), 7.83 (s, 1H), 7.43 (m, 1H), 7.31 (d, J=7.9 Hz, 2H), 7.12 (m, 3H), 4.90 (s, 2H), 2.39 (t, J=7.0 Hz, 2H), 2.09 (m, 21H), 1.62-1.30 (m, 21H), 0.96 (m, 2H), 0.89 (t, J=6.6 Hz, 3H). M− (ESI): 486.6; M+ (ESI): 488.5. HPLC, Rt: 5.8 min (Purity: 100%).