Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O1CCOCC1.[F:8][C:9]1[CH:10]=[C:11]([CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[CH:12]=[CH:13][C:14]=1[CH2:15][O:16][CH2:17][C@@H:18]1[CH2:20][C@@H:19]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[O:31][N:30]=[C:29]([CH:32]([CH3:34])[CH3:33])[N:28]=2)[CH2:23][CH2:22]1>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([CH2:35][C:36]([OH:38])=[O:37])[CH:12]=[CH:13][C:14]=1[CH2:15][O:16][CH2:17][C@@H:18]1[CH2:20][C@@H:19]1[CH:21]1[CH2:22][CH2:23][N:24]([C:27]2[O:31][N:30]=[C:29]([CH:32]([CH3:34])[CH3:33])[N:28]=2)[CH2:25][CH2:26]1
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3COCc3ccc(CC(=O)OC(C)(C)C)cc3F)CC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3COCc3ccc(CC(=O)O)cc3F)CC2)n1
Temperature: 35 °C
Reaction time: 4 h
Yield: 158 %

Procedure:
A solution of 4 M HCl in dioxane (3.85 mL, 15.4 mmol) was added to a solution of tert-butyl 2-(3-fluoro-4-((((1R,2R)-2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)cyclopropyl)methoxy)methyl)phenyl)acetate (Step C product, 750 mg, 1.54 mmol) in DCM (4 mL). This mixture was stirred at 35° C. for 4 hrs. The reaction mixture was subsequently concentrated under reduced pressure to afford the title compound (1.05 g, 97%) as a crude product to be used for the next step. LC/MS (m/z): 432 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[S:11]1[CH:15]=[CH:14][N:13]=[C:12]1[NH2:16].[Na]>C1COCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:16][C:12]2[S:11][CH:15]=[CH:14][N:13]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Nc1nccs1
Agent: [Na]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Nc2nccs2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
A solution of 2-chloro-5-nitropyridine (8.4 g, 53 mmol) and thiazol-2-amine (7.6 g, 76 mmol) in THF (250 mL) is cooled to 0° C. Sodium tert-butoxyde (30% w/w THF, 80 mL) is the added slowly over 15 minutes. The reaction mixture is then warmed slowly to room temperature and stirred 16 hours. The reaction mixture is then poured into a mixture of 1/1 ice/water (1.2 L) with stirring. The solid is filtered and air dried to give a powder (9.74 g, 83%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.17 (d, J=9.35 Hz, 2H), 7.20 (d, J=3.54 Hz, 1H), 7.49 (d, J=3.54 Hz, 1H), 8.43 (dd, J=9.35, 2.78 Hz, 1H), 9.15 (d, J=2.78 Hz, 1H), 12.17 (s, 1H). LCMS (M+H)+: 223.
Reaction SMILES: [C:1]([OH:30])(=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[Sn].[OH:32][CH2:33][CH:34]([CH2:36]O)[OH:35]>>[C:1]([O:30][CH2:36][CH:34]([CH2:33][OH:32])[OH:35])(=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: OCC(O)CO
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Sn]
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO

Procedure:
400 g montanic acid (Hoechst-Wachs S), 97 g glycerol (5% excess) and 0.5 g tin powder were reacted as in Example 1. A yellow, brown-tinged hard wax having a dropping point of 84.2° C. was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Br[C:19]1[CH:32]=[CH:31][C:22]([C:23]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:24])=[CH:21][C:20]=1[F:33].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:17])[CH:4]([N:5]1[CH2:6][CH2:7][N:8]([C:19]2[CH:32]=[CH:31][C:22]([C:23](=[O:24])[NH:25][CH:26]([CH2:27][CH3:28])[CH2:29][CH3:30])=[CH:21][C:20]=2[F:33])[CH2:9][CH2:10]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCC(CC)NC(=O)c1ccc(Br)c(F)c1
Reactant: COC(=O)C(c1ccccc1)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CCC(CC)NC(=O)c1ccc(N2CCN(C(C(=O)OC)c3ccccc3)CC2)c(F)c1
Temperature: 100 °C
Yield: 5.1 %

Procedure:
A mixture of phenyl-piperazin-1-yl-acetic acid methyl ester (80 mg, 0.4 mmol), 4-bromo-N-(1-ethyl-propyl)-3-fluoro-benzamide (prepared as described in Example 113, Step A; 150 mg, 0.5 mmol), Pd2(dba)3 (6 mg, 0.007 mmol), X-Phos (3 mg, 0.007 mmol), and NaOtBu (67 mg, 0.9 mmol) in toluene (5 mL) was heated at 100° C. for 18 h. The solids were removed by filtration and the filtrate was concentrated to give an oil, which was purified by PTLC to give a beige solid (9 mg, 6%). MS (ESI): mass calcd. for C25H32FN3O3, 441.54; m/z found, 442.5 [M+H]+. 1H NMR (CDCl3): 7.46-7.43 (m, 4H), 7.38-7.33 (m, 3H), 6.90 (t, J=8.3, 1H), 5.66 (d, J=8.5, 1H), 4.07 (s, 1H), 3.70 (s, 3H), 3.20-3.18 (m, 4H), 2.65-2.63 (m, 4H), 1.68-1.55 (m, 3H), 1.49-1.42 (m, 2H), 0.93 (t, J=7.4, 6H).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:31][CH3:32])[CH2:20][O:21][CH2:22][C:23]1[CH:24]=[C:25]([CH2:29]O)[CH:26]=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S(Cl)(C)(=O)=O.C(N(CC)CC)C.[Br-:45].[Li+]>O1CCCC1.CCOCC.O>[Br:45][CH2:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][O:21][CH2:20][CH:19]([O:31][CH3:32])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:24]=1
Reactant: CCCCCCCCCCCCCCCCOCC(COCc1cccc(CO)c1)OC
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(CBr)c1)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4 g of 3-[[3-(hexadecyloxy)-2-methoxypropoxy]methyl]benzenemethanol and 3.05 g of mesyl chloride in 40 ml of tetrahydrofuran at 0° C. was added over 20 minutes a solution of 2.69 g of triethylamine in 10 ml of tetrahydrofuran. A 7.71 g portion of lithium bromide was added and the mixture was stirred at room temperature for 2 hours. The solution was diluted with ether, poured into water, and extracted with ethanol. The extract was washed with saturated sodium bicarbonate solution, dried and evaporated, giving the desired compound as an oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+]([O-])=O)[CH:3]=1.BrC1C=CC(C)=C([N+]([O-])=O)C=1.[O-][Mn](=O)(=O)=O.[K+]>O=[Mn]=O.O>[C:6]([OH:8])(=[O:7])[C:5]1[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=[Mn]=O
Agent: Cc1ccc(Br)cc1[N+](=O)[O-]
Solvent: O
Product: O=C(O)c1ccccc1
Yield: 22 %

Procedure:
4-Bromo-2-nitrobenzoic acid. A mixture of 4-bromo-2-nitrotoluene (5.0 g, 23 mmol), KMnO4 (10.9 g, 69 mmol), and water (250 mL) was heated at reflux overnight in a 1 L round-bottom flask fitted with a reflux condenser. The brown suspended MnO2 was removed by filtration through a pad of diatomaceous earth. The filter cake was washed with water. The basic filtrate was acidified to pH˜1 with concentrated HCl and extracted with EtOAc (3×300 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide pure benzoic acid (1.22 g, 22%). 1H NMR (400 MHz, CD3OD): 8.07 (d, J=1.9 Hz, 1H), 7.85 (dd, J=8.2, 1.9 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H). MS (ESI): neg. ion m/z 244 [M−H]−.
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:9]=[CH:8][N:7]=1)[OH:5])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1.O>[CH3:21][S:22]([O:5][CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:9]=[CH:8][N:7]=1)[CH:3]([CH2:1][CH3:2])[CH2:19][CH3:20])(=[O:24])=[O:23]
Reactant: CCC(CC)C(O)c1ncnn1Cc1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCC(CC)C(OS(C)(=O)=O)c1ncnn1Cc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-ethyl-1-[1-(4-fluorobenzyl)-1H-1,2,4-triazol-5-yl]butan-1-ol (0.368 g, 1.32 mmol) in pyridine (15 mL) at 0° C. was added methanesulfonyl chloride (0.61 mL, 7.9 mmol) and the solution was slowly warmed to room temperature. The mixture was diluted with H2O, extracted twice with EtOAc and dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil in quantitative yield.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][C:6](=O)[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:3].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.Cl.C(O)C.[BH4-].[Na+]>CO>[CH3:1][CH:2]([CH3:3])[CH2:4][CH2:5][CH:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CCC(=O)CCC(C)C
Reactant: NCCCCCCCN1CCCCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(C)CCC(CCC(C)C)NCCCCCCCN1CCCCC1

Procedure:
To a solution of 1.70 g of 2,8-dimethylnonan-5-one and 1.98 g of 1-(7-aminoheptyl)piperidine in 50 ml of methanol was added 6 N hydrochloric acid-ethanol to have a pH value of approx. 7 (pH test paper). To the resulting solution was added under cooling 1.26 g of sodium borohydride all at once. The resulting mixture was stirred under chilling with ice for one hour, and then stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was extracted with chloroform after addition of water and an aqueous sodium hydroxide solution. The chloroform portion was dried and evaporated under reduced pressure to remove the solvent, yielding an oily product. The oil product was purified by silica gel column chromatography (eluent: chloroform-methanol 80:1 to 40:1) to give the desired compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].C(=O)([O-])O.[Na+].[CH:25]([Si:28]([C:35]#[CH:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]>[Cl-].[Na+].O.[Cu]I.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.O.O1CCOCC1>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:36]#[C:35][Si:28]([CH:25]([CH3:27])[CH3:26])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: NC(=O)Nc1[nH]c(-c2cccc(Br)c2)cc1C(N)=O
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[Si](C#Cc1cccc(-c2cc(C(N)=O)c(NC(N)=O)[nH]2)c1)(C(C)C)C(C)C
Temperature: 95 °C
Reaction time: 4.5 h

Procedure:
2-Aminocarbonylamino-5-(3-bromophenyl)pyrrole-3-carboxamide (Compound No. 1-31, 200 mg, 0.62 mmol), sodium hydrogencarbonate (133 mg, 1.6 mmol), copper (I) iodide (16 mg, 0.084 mmol), (triisopropylsilyl)acetylene (0.28 mL, 1.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (38 mg, 0.033 mmol) in mixed solvent (12 mL), which consists of water and 1,4-dioxane (1:5), were stirred at 95° C. for 4.5 hours. The brine (5 mL) and water (5 mL) were added to the reaction solution, extracted with ethyl acetate (15 mL), and then the organic layer was dried over magnesium sulfate. The layer was filtered with celite, the solvent was removed under reduced pressure, and then the obtained solid was washed with diethyl ether (2 mL) to give the intermediate 2-aminocarbonylamino-5-(3-triisopropylsilylethynylphenyl)pyrrole-3-carboxamide as a yellow solid. Moreover, 1.0M tetrabutylammonium fluoride in tetrahydrofuran solution (0.48 mL, 0.48 mmol) was added to a solution of this intermediate in tetrahydrofuran (5 mL) and the mixture was stirred at 75° C. for 3.5 hours. The reaction solution was concentrated in vacuo, the obtained residue was purified by silica gel column chromatography to give the target compound (47 mg) as a colorless solid (Yield 29%).
Reaction SMILES: [O:1]([CH2:8][C@H:9]([OH:12])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:14].[Na+]>C(O)(=O)C.O.[Pt]=O>[OH:12][C@@H:9]([CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]([OH:14])=[O:11]
Reactant: OC[C@@H](O)COc1ccccc1
Reactant: O=C([O-])O
Agent: O=[Pt]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)[C@@H](O)COc1ccccc1
Yield: 83 %

Procedure:
Platinum oxide (1.0 g) in acetic acid (20 ml) was hydrogenated at 1 atmosphere for 1.5 h. The platinum was filtered off, washed with water and added to a solution of (R)-3-phenoxy-1,2-propanediol (1.0 g, 6 mmol) and sodium bicarbonate (0.5 g) in water (120 ml). Air was blown through the vigorously stirred mixture overnight. The mixture was filtered, the aqueous solution acidified with hydrochloric acid and extracted with ethyl acetate. The organic extracts were dried (Na2SO4) and the solvent evaporated to give the sub-title acid (0.9 g).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH:23]1([CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(OCC)C.[OH-].[Na+]>ClCCl>[CH:23]1([CH2:29][CH2:30][CH2:31][CH:32]=[O:33])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: OCCCCC1CCCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCCC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
Add Dess-Martin reagent (7.02 g, 16.6 mmol) to a stirred solution of 4-cyclohexyl-1-butanol (2.5 mL, 14.4 mmol) in anhydrous dichloromethane (120 mL). Stir for 3 h at room temperature under nitrogen. Add diethyl ether (200 mL) and 1N sodium hydroxide (150 mL) and stir for 10 minutes. Separate the layers and extract a second time with diethyl ether (100 mL). Combine the diethyl ether extracts, wash with 1N sodium hydroxide (100 mL), dry over magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 2.01 g (90%) of 4-cyclohexyl-butyraldehyde: 1H NMR (CDCl3): 9.76 (s, 1H), 2.41-2.37 (m, 2H), 1.71-1.58 (m, 7H), 1.27-1.07 (m, 6H), 0.93-0.82 (m, 2H).
Reaction SMILES: [N:1]([N:3]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2)=O.[Cl-].[NH4+].O.[CH3:22][C:23]([CH3:25])=O>[Zn]>[CH3:22][C:23](=[N:1][N:3]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2)[CH3:25]
Reactant: CC(C)=O
Reactant: O=NN1CC(c2ccncc2)Sc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: CC(C)=NN1CC(c2ccncc2)Sc2ccccc21
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-nitroso-2-(pyridin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (0.3 g, 0.00116 mol) in acetone (12 mL) was added saturated ammonium chloride solution (3 mL) and water (3 mL) at RT, and the resulting brown colored reaction mixture was cooled to −5° C. Zinc dust (0.15 g, 0.00233 mol) was added portionwise at the same temperature and stirred for 10 min. After completion of reaction (monitored by TLC), solvent was removed under reduced pressure and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to obtain product as a brown colored oil (0.25 g).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:6]=[N:7][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:10]=1[C:11]#[N:12]>N1C=CC=CC=1>[C:13]1([C:8]2[CH:9]=[C:10]3[C:11]([NH2:12])=[N:7][NH:6][C:5]3=[N:2][N:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cc(-c2ccccc2)nnc1Cl
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: Nc1n[nH]c2nnc(-c3ccccc3)cc12

Procedure:
Hydrazine hydrate (0.7 ml, 14.3 mmol) was added to a stirred solution of 3-chloro-6-phenyl-pyridazine-4-carbonitrile (cf J. Med. Chem., 1999, 42, 730; 1.024 g, 4.7 mmol) in pyridine (10 ml). The reaction mixture was stirred at reflux for 6 hours, cooled and the resulting solid was filtered and dried in vacuo, affording the title compound as a solid.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[C:11]([OH:12])[C:10]=1[OH:19])([O-:8])=[O:7]>CC(OC(C)=O)=O>[C:11]([O:12][C:11]1[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=[C:9]([N+:6]([O-:8])=[O:7])[C:10]=1[O:19][C:10](=[O:19])[CH3:9])(=[O:12])[CH3:13]
Reactant: O=[N+]([O-])c1cc(O)c(O)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1OC(C)=O
Temperature: 0 °C

Procedure:
A catalytic amount of concentrated sulfuric acid was added to a solution containing 2.0 g of 3,5-dinitrocatechol in 15 ml of acetanhydride and the solution was mixed for 1/2 hours in 50°-60° C. Ice water wasadded to the rection mixture and the solution was mixed in 0° C. whereby the product was crystallized. The product was filtered and washed with water and dried. Yield 2.75 g (97%), m.p. 115°-117° C.
Reaction SMILES: [CH:1]([OH:6])([OH:5])[C:2]#[C:3][CH3:4].[H][H].[CH2:9]([OH:13])[CH2:10][CH2:11][CH3:12]>>[CH:1]([OH:6])([OH:5])[C:2]#[C:3][CH3:4].[CH2:12]([OH:5])[CH2:11][CH2:10][CH2:9][OH:13]
Reactant: CCCCO
Reactant: [H][H]
Agent: CC#CC(O)O
Product: OCCCCO

Procedure:
The procedure of Example 5 was repeated with 5 g of Raney Ni/Mo being installed. 100 g/h of butynediol solution were hydrogenated at a reactor temperature of about 122° C., 20 bar and 300 l/h of hydrogen. At a space velocity of liquid of 225 m3/m2·h and a kLa of 0.3 s−1 and complete butynediol conversion, n-butanol contents in the product of 2.2-2.7% by weight were obtained, with the 1,4-butanediol content being 77% by weight and the remainder being intermediates. After increasing the space velocity of liquid to 263 m3/m2h, corresponding to a kLa of 0.4 s−1, the n-butanol content fell to 1.3% by weight, the butanediol content rose to 88% by weight.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=4)[CH2:12][NH:11][CH2:10]3)[O:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(C2CNCC(c3nc(C4CC4)no3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.23 g (7.38 mmol) of the compound from Example 182A were initially charged in 60 ml of dichloromethane and, at RT, reacted with 5.7 ml (8.42 g, 73.8 mmol) of trifluoroacetic acid. The reaction mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 2.48 g (92% of theory)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.N1C=CC=CC=1[CH:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[CH2:23][CH2:24][C:25]#[CH:26]>C(N(CC)CC)C.C(#N)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>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]#[C:25][CH2:24][CH2:23][N:18]2[CH2:17][CH2:22][N:21]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:20][CH2:19]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: C#CCCN1CCNCC1c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C#CCCN2CCN(c3ccccn3)CC2)nc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2-bromo-5-nitropyridine (3.11 g, 0.015 mol) and the alkyne prepared in Step (a) (3.0 g, 0.014 mol) in 5.8 mL of triethylamine and 60 mL of acetonitrile is degassed by bubbling in dry nitrogen for 15 minutes, and 0.2 g (0.0003 mol) of bis(triphenylphosphine)palladium chloride and 0.05 g (0.0003 mol) of cuprous iodide are added. The flask is flushed with nitrogen and the mixture is stirred at room temperature for 5 hours. The solvent is removed under reduced pressure, and the residue is partitioned between 50 mL of dichloromethane and 50 mL of saturated aqueous sodium bicarbonate. The aqueous layer is extracted with 30 mL of dichloromethane and the combined organic layers are washed with water and dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 1% methanol/ 99% dichloromethane) to give the title compound as a brown solid; mp 126°-126.5° C.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>CCOC(C)=O.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>[F:15][C:14]([F:17])([F:16])[O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[CH:6][C:2]([C:23]3[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=3)=[CH:3]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(-n2ccc(Br)c2)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ccn(-c3ccc(OC(F)(F)F)cc3)c2)cc1
Temperature: 150 °C
Yield: 18.9 %

Procedure:
A suspension of crude 3-bromo-1-(4-trifluoromethoxyphenyl)-1H-pyrrole (356 mg, 1.26 mmol, 1.00 eq), 4-formylphenylboronic acid (283 mg, 1.89 mmol, 1.50 eq), bis(triphenylphosphine)palladium(II) dichloride (27 mg, 0.04 mmol, 0.03 eq), 2M Na2CO3 (aq) (1.26 mL, 2.52 mmol, 2.0 eq), and 1,4-dioxane (5 mL) were heated at 150° C. in a microwave reaction vessel for 45 min. The cooled solution was then diluted with EtOAc (20 mL), filtered over Celite®, concentrated to dryness, and purified via chromatography (2:2:1, hexane:EtOAc:acetone) to afford the desired intermediate (79 mg, 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]([O:19]C)=[O:18])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:16]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]([OH:19])=[O:18])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:16]=1
Reactant: COC(=O)c1cc(Cl)cc2nc(-c3ccccc3)oc12
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cc(Cl)cc2nc(-c3ccccc3)oc12
Yield: 82 %

Procedure:
5-Chloro-2-phenylbenzoxazole-7-carboxylic acid was prepared from methyl 5-chloro-2-phenyl-benzoxazole-7-carboxylate via lithium hydroxide mediated hydrolysis as described in Step B of Example 14. This material was obtained as a white solid in 82% yield. 1H NMR (300 MHz, DMSO-d6) δ 13.84 (br s, 1H), 8.22-8.19 (m, 3H), 7.85 (d, J=2.1 Hz, 1H), 7.70-7.63 (m, 3H), 4.07 (s, 3H); MS (ESI) m/z 274 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](O)[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)([Cl:32])=O>>[F:1][C:2]([F:21])([F:20])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([Cl:32])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1Cl
Yield: 57.8 %

Procedure:
A mixture of 5.0 g (0.016 mol) of product of Example 35, 4.52 g (0.0362 mol) of 2,6-lutidine and 34 ml of phosphorus oxychloride was held at reflux for 20 hours and concentrated in vacuo. The residue was quenched with water and extracted with ether. The ether extract was washed successively with 10% K2CO3 and water, dried (CaSO4) and concentrated in vacuo to give 3.06 g (57.8%) of product as a brown oil, nD25 1.4313.