Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.[CH:19](=O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(O)C>[CH2:19]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:15])([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:17][CH:18]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCC=O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Solvent: CCO
Product: CCCCCCCNCCc1ccc(OC(C)(C)C(=O)OCC)cc1
Yield: 100.7 %

Procedure:
The product from step (c) (1.5 g) and heptaldehyde (0.7 g) were mixed together in a observably exothermic reaction and the product dissolved in absolute ethanol (100 ml). Paar hydrogenation for 1.0 hour resulted in a drop in bottle pressure from 49.0 to 42.7 psi. The Pd/C was removed by filtration and the filtrate evaporated in vacuo to give the desired product as a colourless oil (2.1 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:12].C(N(CC)CC)C.[CH3:20][CH:21]([OH:24])[C:22]#[CH:23]>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[N:10]=[C:9]([C:23]#[C:22][CH:21]([OH:24])[CH3:20])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:12]
Reactant: C#CC(C)O
Reactant: Cn1cnc2c(Cl)nc(I)nc21
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(O)C#Cc1nc(Cl)c2ncn(C)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-chloro-2-iodo-9-methyl-9H-purine (6.8 g, 23.3 mmol), CuI (454 mg, 2.23 mmol) and bis-triphenylphosphine palladium dichloride (811 mg, 1.15 mmol) in dioxane (93 ml) were added triethylamine (4.9 ml, 34.5 mmol) and but-3-yn-2-ol (1.1 ml, 25.63 mmol). The reaction mixture was stirred at RT for 1 h. The volatiles were removed under reduced pressure. Water (50 ml) was added to the dark residue obtained. The aqueous phase was extracted with DCM (3×100 ml). The combined organic phases were dried over anhydrous sodium sulphate and evaporated under reduced pressure. The combined organic phases were dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH: 94/6).
Reaction SMILES: CO[C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:20][NH:21][C:22]([NH2:24])=[O:23].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[C:3]([NH:24][C:22]([NH:21][CH3:20])=[O:23])=[O:19])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCC1)c1ccc(F)c(F)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(F)c(F)c1
Temperature: 100 °C
Yield: 9.4 %

Procedure:
A mixture of 3-cyclopentyl-2-(3,4-difluoro-phenyl)-propionic acid methyl ester (1.65 g, 6.14 mmol) and methyl urea (683 mg, 9.22 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 16.6 mL, 12.3 mmol) was refluxed at 100° C. for 8 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(3,4-difluoro-phenyl)-propionyl]-3-methyl-urea (180 mg, 9.4%) as a white solid: mp 111-113° C.; EI-HRMS m/e calcd for C16H20F2N2O2 (M+) 310.1493, found 310.1499.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Si]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[C:26]=2[CH3:38])=[CH:21][CH:20]=1)(C(C)(C)C)(C)C.[CH3:39]I.O>O1CCCC1>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:39])[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[C:26]=2[CH3:38])=[CH:23][CH:24]=1
Reactant: C=CCOC(=O)Cc1cccc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c1C
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)C(C)c1cccc(-c2ccc(O)cc2)c1C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
A bis(trimethylsilyl)amide lithium-11.0M tetrahydrofuran solution (2.47 ml, 2.47 mmol) was added dropwise to a solution of allyl (4′-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl-1,1′-biphenyl-3-yl)acetate (675 mg, 1.70 mmol) obtained in Example (98-2) in tetrahydrofuran (6 ml) at −78° C. After the mixture was stirred for 30 minutes, methyl iodide (512 μl, 8.22 mmol) was added thereto and the mixture was stirred at −78° C. for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was dissolved in tetrahydrofuran (5 ml). A tetra-n-butylammonium fluoride-1.0M tetrahydrofuran solution (2.04 ml, 2.04 mmol was added to the solution and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel preparative thin layer chromatography (developing solvent: n-hexane/ethyl acetate=3/1) to give allyl 2-(4′-hydroxy-2-methyl-1,1′-biphenyl-3-yl)propanoate (457 mg, yield: 91%).
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:11][S:12](O)(=[O:14])=[O:13].O=S(=O)=O>>[OH:1][C:2]1[N:10]=[CH:9][C:8]([S:12]([OH:14])(=[O:13])=[O:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)c1cccnc1O
Agent: O=S(=O)=O
Product: O=C(O)c1cc(S(=O)(=O)O)cnc1O
Temperature: 140 °C
Yield: 82.9 %

Procedure:
2-Hydroxynicotinic acid (27 Kg, 194.2 mol) was added portionwise to 30% oleum (58.1 Kg) at 50° C. over 1 hr. This caused an exotherm to 82° C. The reaction mixture was heated further to 140° C. After maintaining this temperature for 12 hrs the reactor contents were cooled to 15C and filtered. The filter cake was then re-slurried with acetone (33 Kg) at room temperature, filtered and dried to afford the title compound (35.3 Kg, 83%) as a white solid. Decomposition pt 273° C. δ (DMSOd6): 7.93 (1H, d), 8.42 (1H, d). m/z (Found: 220 [M+H]+, 100%. C6H6NO6S requires 220.17).
Reaction SMILES: C[N:2]([CH3:13])[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11].[OH:14][CH:15]([CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:16]C#N>>[OH:14][CH:15]([CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:16][C:13]1[NH:2][C:3](=[O:12])[C:4]2[C:5]([CH:11]=1)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=2
Reactant: Cc1cccc(C(=O)N(C)C)c1C
Reactant: N#CCC(O)CN1CCCC1
Product: Cc1cccc2c(=O)[nH]c(CC(O)CN3CCCC3)cc12
Yield: 1.5 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-dimethyl-2,3-dimethylbenzamide (2.65 g) and 3-hydroxy-4-(pyrrolidin-1-yl)butyronitrile (2.31 g), 3-[2-hydroxy-3-(pyrrolidin-1-yl)propyl]-5-methyl-2H-isoquinolin-1-one (0.066 g) was obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:7]3=[N:8][C:9]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[N:11]=[C:6]3[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>CCO>[CH:1]1([C:4]2[N:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:7]3=[N:8][C:9]([C:19]4[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=4)=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=4)[N:11]=[C:6]3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CCCCCCn1c(C2CC2)cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc3cc(C4CC4)n(CCCCCCC(=O)O)c3nc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 7-(6-cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate (Step 6) (230 mg, 0.464 mmol) in EtOH (4 ml) was treated with 2M NaOH (0.696 ml, 1.392 mmol) and stirred at room temperature for 16 hours. The reaction mixture was added to water (50 ml) and the pH was adjusted to pH 1 by addition of 2M HCl. The resulting suspension was filtered, washed with water (×3) and dried under vacuum. The resultant residue was dissolved in EtOH (minimal) and excess water added. The resultant aqueous was then extracted with DCM (×3), and the organic solvent removed under reduced pressure. The resultant residue was then taken in diethyl ether, sonicated and the solvent removed under reduced pressure. Further diethyl ether was added, sonicated and the solvent removed under reduced pressure. The resultant residue was dissolved in EtOAc (minimal) and excess iso-hexane was added. The resultant suspension was filtered, the filter cake washed with iso-hexane (×4) and dried to afford the titled compound as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH:11]([N:14]=[C:15]=[O:16])([CH3:13])[CH3:12].C(N(CC)CC)C>C1C=CC=CC=1>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][O:1][C:15](=[O:16])[NH:14][CH:11]([CH3:13])[CH3:12]
Reactant: O=C(CO)c1ccccc1
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)NC(=O)OCC(=O)c1ccccc1
Yield: 36.9 %

Procedure:
A mixture of α-hydroxyacetophenone (7.0 g, 51.4 mmol), isopropyl isocyanate (10.1 ml, 102.8 mmol) and triethylamine (7.2 ml, 51.4 mmol) in 150 ml of benzene was refluxed under nitrogen overnight. The reaction was diluted with benzene, extracted with 1N HCl, dried (MgSO4) and the solvent removed under reduced pressure to 9.741 g of a brown solid. Recrystallization of the solid from isopropyl alcohol gave isopropyl-carbamic acid 2-oxo-2-phenyl-ethyl ester (4.2 g, 38%) as yellow solid, mp 108-110° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CN(C)C=O.[Cu]I>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[NH:19][C:14]2[C:13]([CH:12]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCC#Cc1ccccc1N
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1cc2ccccc2[nH]1

Procedure:
2-[4-(tert-Butyldimethylsilanyloxy)but-1-ynyl]phenylamine (8 mmol) was heated at reflux in N,N-dimethylformamide (30 mL) with copper(I) iodide (5 mg, 0.026 mmol) for 3 hours. The solvent was evaporated, and the residue was diluted with ether and filtered through Celite. The filtrate was concentrated, and the residue was purified by SiO2 chromatography (5-20% ethyl acetate/hexanes) to give the desired product, 0.88 g. 1H NMR (300 MHz, CDCl3) d 8.62 (br, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.13-7.03 (m, 2H), 6.22 (s, 1H), 3.92 (t, J=5.7 Hz, 2H), 2.95 (t, J=5.7 Hz, 2H), 0.95 (s, 9H), 0.08 (s, 6H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10](Cl)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[NH:15][NH2:16]>C(O)CCC>[C:1]1([C:7]2[N:12]=[N:11][C:10]([NH:16][NH:15][C:14]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)NN
Reactant: Clc1ccc(-c2ccccc2)nn1
Solvent: CCCCO
Product: CCOC(=O)NNc1ccc(-c2ccccc2)nn1

Procedure:
A mixture of 15.0 g. of 6-phenyl-3-chloropyridazine, 16.3 g. of ethyl carbazate, and 250 ml. of n-butanol is refluxed for 3 hours. The solvent is removed under vacuum and the residue triturated with cold water. Filtration gives 18.6 g. of cream colored crystals. Recrystallization gives white crystals, m.p. 158°-160° C.
Reaction SMILES: O([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)C1C=CC=CC=1.[NH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][OH:28]>>[CH:18]1[C:19]2[C:14](=[N:13][C:12]3[C:21]([C:20]=2[NH:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][OH:28])=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:15]=[CH:16][CH:17]=1
Reactant: NCCNCCO
Reactant: c1ccc(Oc2cccc3nc4ccccc4cc23)cc1
Product: OCCNCCNc1c2ccccc2nc2ccccc12

Procedure:
A mixture of phenoxyacridine (S1) (2.71 g, 0.01 mol) and 2-(2-aminoethylamino)ethanol (S3)
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][O:20][CH3:21])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:22]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)=[CH:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:24]1([CH:23]=[C:22]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([CH2:19][O:20][CH3:21])[CH:18]=[C:13]3[CH:12]=2)[C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COCc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 91.8 %

Procedure:
A solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxymethyl-1H-pyrrolo[2,3-b]pyridine (600 mg, 1.09 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 5 mL, 5 mmol) was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxymethyl-1H-pyrrolo[2,3-b]pyridine (411 mg, quant.) as a white solid: LC/MS m/e calcd for C23H26N2O3S [M+H]+ 411.54, observed 411.1.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:3]=1[NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[N:6]=1.[CH2:20](Cl)[C:21]#[CH:22]>>[Br:1][C:2]1[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:3]=1[N:4]([CH2:22][C:21]#[CH:20])[C:5]1[N:6]=[C:7]([CH3:12])[CH:8]=[C:9]([CH3:11])[N:10]=1
Reactant: Cc1cc(C)nc(Nc2ccc(C(C)C)cc2Br)n1
Reactant: C#CCCl
Product: C#CCN(c1nc(C)cc(C)n1)c1ccc(C(C)C)cc1Br

Procedure:
By using 2-(2-bromo-4-(1-methylethyl)anilino)-4,6-dimethylpyrimidine and substituting propargyl chloride in Example 9, the title compound was isolated as the free-base, Mass spec. (NH3 --CI/DDIP): 358 (m+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[N:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH2:31])=[CH:28][CH:29]=2)[CH:24]=[N:23]1.C(O)(C(F)(F)F)=O>CS(C)=O>[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:2]3[N:7]=[C:6]4[NH:8][N:9]=[CH:10][C:5]4=[C:4]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=4)[N:3]=3)=[CH:28][CH:29]=2)[CH:24]=[N:23]1
Reactant: NS(=O)(=O)c1ccc(Nc2nc(Cl)nc3[nH]ncc23)cc1
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: NS(=O)(=O)c1ccc(Nc2nc(Nc3ccc4[nH]ncc4c3)nc3[nH]ncc23)cc1
Temperature: 120 °C
Yield: 99 %

Procedure:
Compound 4A, 1H-indazol-5-ylamine Compound 5A and TFA (94 ul, 1.1 mmol) were mixed in dry DMSO (1 ml) and heated to 120° C. for 48 hours to provide Compound 12 (99% yield). 1HNMR (CD3OD) δ 8.5 (s, 1H), 8.12 (s, 2H), 7.9 (m, 2H), 7.7 (d, 2H), 7.5 (d, 2H); MS 536 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([O:14][CH3:15])[CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(F)nc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-fluoronicotinic acid (10 g, 70.9 mmol) in DCM (200 ml), was added N,O-Dimethylhydroxylamine hydrochloride (7.3 g, 74.8 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (15 g, 78.5 mmol), and triethylamine (22 ml, 156 mmol). The reaction mixture was allowed to stir at room temperature for 16 hours. The reaction was partitioned with water, layers were cut, and organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue obtained was purified by a silica gel filtration using EtOAc-DCM (4:1) to give 7.2 g (55% isolated yield) of the title compound. 1H NMR: 8.48 (s, 1H) 8.21 (t, J=8.29 Hz, 1H) 7.27 (dd, J=8.29, 3.01 Hz, 1H) 3.54 (s, 3H) 3.27 (s, 3H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].N1C=CC=CC=1.[C:15](Cl)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])O.[Na+]>C(OCC)C>[C:15]([O:3][C:2](=[CH2:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)C(C)=O
Reactant: CCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=C(OC(=O)CCCCCCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
While ethyl pyruvate (174 g, 1.5 mol) was being stirred at 0° C., pyridine (120 g, 1.5 mol) was dropped into the ethyl pyruvate. After it was stirred at 0° C. for 10 minutes, octanoyl chloride (243 g, 1.5 mol) was slowly dropped into this mixture. After the temperature of the reaction solution reached room temperature, the reaction solution was stirred for 48 hours. An aqueous solution of saturated sodium hydrogencarbonate and diethyl ether were added to the reaction solution, and an organic layer was separated by use of a separating funnel. Diethyl ether was again added to an aqueous layer and an organic compound was extracted. The obtained organic layer was then mixed with the organic compound, and sodium sulfate was added for dehydration. Thereafter, the sodium sulfate was removed by filtration and the solvent was removed by use of an evaporator under a reduced pressure. The concentrate was distilled under a reduced pressure (1 mmHg, 95 to 100° C.) to give ethyl α-octanoyloxyacrylate (126 g, yield: 34%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH3:10])[C:4]=1[S:11]([NH:14]C(C)(C)C)(=[O:13])=[O:12]>FC(F)(F)C(O)=O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH3:10])[C:4]=1[S:11]([NH2:14])(=[O:12])=[O:13]
Reactant: CSc1cccc(SC)c1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CSc1cccc(SC)c1S(N)(=O)=O
Reaction time: 0.17 h
Yield: 84 %

Procedure:
A brown solution of 70 g of 2,6-bis(methylthio)-N-(1,1-dimethylethyl)benzenesulfonamide in 200 ml trifluoroacetic acid was stirred at room temperature. After 10 minutes, a heavy precipitate formed, the suspension was stirred for 18 hours. The resulting solid was collected by filtration and dissolved in 10% NaOH, filtered and the filtrate acidified with 10% HCl. The precipitated solid was washed with water and air dried to provide 48 g of 2,6-bis(methylthio)benzenesulfonamide, m.p. 197°-199°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.[Cl:28]C1C=C(C=CC=1OCC1C=CC2C(=CC=CC=2)N=1)C(N(OC)C)=O>>[Cl:28][C:14]1[CH:15]=[C:10]([C:8](=[O:9])[CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:11]=[CH:12][C:13]=1[O:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1

Procedure:
Following the procedure for the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but substituting 3-Chloro-N-methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide provided the title compound. (M+H m/z=389.0).
Reaction SMILES: Br[C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=[O:4].[CH:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19].C(N(CC)CC)C.[Al]>C1COCC1.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.[Cu]I>[C:6]1(/[CH:5]=[C:2](\[C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19])/[CH:3]=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCCCCC#C
Reactant: O=CC(Br)=Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Al]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCCCCC#C/C(C=O)=C\c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of Pd(PPh3)4 (0.55 g, 0.24 mmol) and α-bromocinnamaldehyde Compound 1 (2.08 g, 4.74 mmol) in degassed THF (170 mL) cooled in an ice-water bath was added a solution of 1,7-octadiyne (2.23 g, 9.48 mmol), triethylamine (15 mL), and CuI (0.36 g, 0.95 mmol) in degassed THF (30 mL) via a syringe under a nitrogen atmosphere. The reaction flask was then covered by a sheet of aluminum foil. After stirring at room temperature for 8 hours the reaction was quenched with saturated aqueous NH4Cl (50 mL) and diluted with EtOAc (100 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 10 percent EtOAc in hexane) to give 2.13 g (91 percent) of Compound 2: yellow oil; Rf=0.50 (15 percent EtOAc in hexane); IR (neat) 3294, 2944, 2230, 2116, 1692, 1598, 1450, 1324, 1180 cm−1; 1H NMR (300 MHz, CDCl3) δ9.56 (s, 1H), 8.11-8.07 (m, 2H), 7.48-7.43 (m, 3H), 7.43 (s, 1H), 2.60 (t, J=6.65 Hz, 2H), 2.27 (td, J=6.78, 2.64 Hz, 2H), 1.97 (t, J=2.64 Hz, 1H), 1.86-1.69 (m, 4H); 13C NMR (75 MHz, CDCl3) δ192.4, 151.8, 134.9, 132.0, 131.1, 129.4, 124.1, 103.4, 84.6, 75.4, 69.4, 28.2, 28.0, 20.3, 18.7; MS (+FAB) m/z (relative intensity) 237 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([C:5]1[C:9]([CH3:10])=[CH:8][NH:7][N:6]=1)=[O:4].C1C(=O)N([I:19])C(=O)C1>CC#N>[I:19][C:8]1[NH:7][N:6]=[C:5]([C:3]([N:2]([CH3:11])[CH3:1])=[O:4])[C:9]=1[CH3:10]
Reactant: Cc1c[nH]nc1C(=O)N(C)C
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Cc1c(C(=O)N(C)C)n[nH]c1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
To a solution of N,N,4-trimethyl-1H-pyrazole-3-carboxamide (compound 374.1, 0.98 g, 6.40 mmol) in CH3CN (10 mL) was added NIS (1.59 g, 7.04 mmol). The mixture was stirred at room temperature for 16 hours then quenched with sat. Na2SO3 solution (5 mL). The mixture was partitioned between EtOAc (200 mL) and water (30 mL). The EtOAc layer was washed with brine (30 mL), dried (MgSO4) and concentrated. The residue was purified with column chromatography (50% EtOAc in hexanes to 100% EtOAc) to give the product as a brown solid (1.79 g, 100%). m/z (ES+) 280 (M+H)+.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:40]([O:42][CH3:43])=[O:41]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH3:43])=[O:41])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC)cc1)n2C)c1ccccc1
Yield: 41 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and methyl chloroformate. Yield: 41% of theory, C30H32N6O5 (556.6) Rf value: 0.85 (silica gel; dichloromethane/ethanol=4:1) ##EQU62##