Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]4[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=4)[CH:16]=3)[S:11][C:10]([CH3:32])([CH3:31])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]4[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=4)[CH:16]=3)[S:11][C:10]([CH3:32])([CH3:31])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)nc2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cn1
Temperature: 35 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of ethyl 4-[[4-(6-methylpyridin-3-yl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate (Compound 233, 70.0 mg, 0.159 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). The resulting solution was stirred overnight at 35° C. Upon cooling to room temperature, the reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from acetone to give 60.0 mg (92%) of the title compound as a colorless solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.36 (1H, d, J=2.1 Hz), 7.91 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz), 7.56 (1H, dd, J=2.1 8.0 Hz), 7.45 (2H, m), 7.31 (1H, d, J=8.0 Hz), 7.06 (1H, s), 6.06 (1H, s), 2.51 (3H, s), 1.44 (6H, s).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[NH:4][CH3:5].Br.Br[CH:14]([C:16]1[CH:17]=[C:18]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH:19]=[C:20]2[C:25]=1[O:24][C:23]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[CH:22][C:21]2=[O:32])[CH3:15]>>[CH3:36][N:35]([CH3:37])[C:33]([C:18]1[CH:19]=[C:20]2[C:25](=[C:16]([CH:14]([N:4]([CH3:5])[C:3]3[CH:6]=[C:7]([F:11])[CH:8]=[C:9]([F:10])[C:2]=3[F:1])[CH3:15])[CH:17]=1)[O:24][C:23]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[CH:22][C:21]2=[O:32])=[O:34]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CNc1cc(F)cc(F)c1F
Agent: Br
Product: CC(c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1F
Yield: 7.9 %

Procedure:
2,3,5-trifluoro-N-methylaniline (197 mg, 1.22 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (150 mg, 0.31 mmol) using an analogous procedure to the one described in Example 3.03 to give N,N-dimethyl-8-(1-(methyl(2,3,5-trifluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (12 mg, 8%) as a white solid. Mass Spectrum: M+H+ 490.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:27]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[O:7][NH:27]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccccc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 77.4 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-phenylpiperidine-1-carboxylate (1.913 g, 5.74 mmol) was dissolved in MeOH (15 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.230 g, 5.74 mmol) dissolved in water (1.500 mL) was added during 5 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.352 mL, 5.74 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 2 h 15 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (24 mL, 144.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase evaporated to yield a slightly yellow oil. The compound was purified by preparative HPLC in 2 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-phenylpiperidine-1-carboxylate (1.344 g, 77%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.77-1.85 (m, 1H), 2.10-2.18 (m, 1H), 2.19-2.28 (m, 1H), 2.32-2.39 (m, 1H), 3.01-3.08 (m, 1H), 3.37 (ddd, 1H), 3.64 (s, 3H), 4.15 (ddd, 1H), 5.08-5.13 (m, 1H), 5.48 (s, 1H), 7.13-7.20 (m, 3H), 7.27 (t, 2H). MS m/z 303 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:5][C:4]=1[C:19]([O:21]C)=[O:20].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([S:13]([N:16]([CH3:17])[CH3:18])(=[O:15])=[O:14])=[CH:5][C:4]=1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1cc(S(=O)(=O)N(C)C)c2ccccc2c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C(=O)O)cc(S(=O)(=O)N(C)C)c2ccccc12

Procedure:
A solution of methyl 1-methoxy-4-(N,N-dimethylaminosulfonyl)-2-napthalenecarboxylate (2.3 g; 7.13 mmol; 1 eq) is refluxed in 50% ethanol with 428 mg of NaOH (10.71 mmol; 1.5 eq) for 2 h. Next, the solvent is evaporated off under vacuum and the residue is taken up in water and extracted once with ethyl acetate. 1N HCl is added to the aqueous phase to pH 1-2. The mixture is extracted twice with dichloromethane, dried and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([O:19][CH3:20])=[C:16]([Cl:18])[CH:17]=1)[C:5]#[N:6].C(=O)([O-])[O-:22].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([O:19][CH3:20])=[C:16]([Cl:18])[CH:17]=1)[C:5]([NH2:6])=[O:22]
Reactant: COc1ncc(COc2ccc(C#N)cc2Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ncc(COc2ccc(C(N)=O)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a suspension of 3-chloro-4-[(5-chloro-6-methoxypyridin-3-yl)methoxy]benzonitrile (Preparation 30, 64 mg, 0.21 mmol) and potassium carbonate (57 mg, 0.414 mmol) in DMSO (5 mL) was added hydrogen peroxide (141 mL, 4.14 mmol) and the reaction stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL) and extracted with EtOAc (10 mL). The organic layer was washed with water (2×10 mL), dried over sodium sulfate and concentrated in vacuo to afford a white solid, which was triturated with EtOAc to yield the title compound (30 mg, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]2[C:27]([OH:29])=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH:30][NH:31]C(C1C(COCC2C=CC=CC=2)CCCCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O>>[OH:30][NH:31][C:27]([CH:13]1[CH:14]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:16][CH2:17][CH2:18][N:12]1[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])=[O:29]
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(C=Cc3ccccc3)C2C(=O)O)cc1
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(COCc3ccccc3)C2C(=O)NO)cc1
Product: COc1ccc(S(=O)(=O)N2CCCCC(C=Cc3ccccc3)C2C(=O)NO)cc1

Procedure:
1-(4-Methoxy-benzenesulfonyl)-3-styryl-azepane-2-carboxylic acid hydroxyamide was synthesized from 1-(4-Methoxy-benzenesulfonyl)-3-styryl-azepane-2-carboxylic acid in the same manner as the procedures used for the preparation of 3-Benzyloxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid hydroxyamide: MS (M+H)+ =431, (M+NH4)+ =448, (M-H)- =429.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1[N:17]=[N:18][N:19](CCCC=CC)[N:20]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:5]1[N:14]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:31][CH:30]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:16]3[N:17]([CH2:10][CH2:11][CH2:12][CH2:7][CH:8]=[CH2:9])[N:18]=[N:19][N:20]=3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC=CCCCn1nnc(-c2ccc3[nH]c(CCCC)nc(=O)c3c2)n1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCCCCn1nnnc1-c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C#N)cc3)c(=O)c2c1
Yield: 175.4 %

Procedure:
A mixture of 1.7 g of 2-butyl-6-[2-(4-hexenyl)-2H-tetrazol-5-yl]-4(1H)-quinazolinone, 1.9 g of 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile and 3.0 g of potassium carbonate in 100 ml of acetone is refluxed for 24 hours. The reaction mixture is filtered and the filtrate evaporated to a residue which is purified by chromatography on silica gel by elution with 30% ethyl acetate-hexanes to give 2.3 g of the desired product as a yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([CH2:41][NH2:42])[CH2:40][CH2:39]1>>[CH:38]1([CH2:41][NH:42][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:40][CH2:39]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: NCC1CC1
Product: O=C(Nc1ccc(Oc2ccnc(NCC3CC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and cyclopropylmethylamine according to conditions described in general procedure C. Mp: 116-117° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.1-0.3 (m, 4 H), 0.97 (bs, 1 H), 2.75-3.02 (m, 2 H) 3.26 (s, 4 H), 3.76 (s, 4 H), 6.25 (bd, 1 H), 7.03 (d, J=12.4 Hz, 1 H), 7.24-7.27 (m, 2 H), 7.38-7.41 (m, 1 H), 7.48 (s, 1 H), 7.56-7.59 (m, 3 H), 7.80-7.83 (m, 1 H), 7.98 (d, J=7.3 Hz, 1 H), 8.20 (s, 1 H), 10.45 (s, 1 H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14]1[CH:15]=[C:16]([CH:20]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[C:21]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[N:22]=2)[CH:17]=[CH:18][CH:19]=1>CN(C=O)C>[CH3:37][N:34]1[CH2:35][CH2:36][CH:31]([O:30][CH:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][N:2]3[N:3]=[CH:4][CH:5]=[N:1]3)[CH:15]=2)[C:21]2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:32][CH2:33]1
Reactant: CN1CCC(OC(c2cccc(C#CCCCCl)c2)c2nc3ccccc3[nH]2)CC1
Reactant: c1c[nH]nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(OC(c2cccc(C#CCCCn3nccn3)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,2,3-triazole (66 mg) in DMF (0.6 mL) is added sodium hydride (25 mg). After gas evolution ceased, 2[[3-(5-chloropent-1-ynyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (50 mg) and a catalytic quantity of n-tetrabutylammonium iodide are added. After stirring overnight at room temperature, the solvent is removed under reduced pressure to dryness. The residue is purified by chromatography (dichloromethane/methanol/ammonia 90/10/1) to afford 2-{(1-methylpiperidin-4-yloxy)[3-(5-[1,2,3]triazol-2-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazole.
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]([F:30])[CH:18]=1)=O)(C)(C)C>ClCCl.C([O-])(O)=O.[Na+]>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH2:15])=[CH:18][C:19]=1[F:30])=[O:29]
Reactant: CC(C)(C)CC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)CC(=O)c1ccc(CN)cc1F
Reaction time: 4 h
Yield: 85.2 %

Procedure:
Add 4N hydrogen chloride in dioxane (2.7 mL, 10.8 mmol) to a solution of N-(tert-butoxycarbonyl)-4-(3,3-dimethyl-butyryl)-3-fluoro-benzylamine (296 mg, 0.92 mmol) in dichloromethane (11 mL) and stir for 4 h. Concentrate in vacuo and wash the solid obtained with diethyl ether. Suspend the solid in saturated aqueous NaHCO3 and stir for 30 min. Extract twice with dichloromethane. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the title compound as an oil (175 mg, 82%).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:9]=[CH:10][CH:11]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]2[N:4]([N:9]=[CH:10][CH:11]=2)[CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(Br)c2ccnn2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cc(OCc2ccccc2)cn2nccc12
Reaction time: 0.17 h

Procedure:
4-bromopyrazolo[1,5-a]pyridin-6-ol (50.0 mg, 0.235 mmol) was dissolved in DMF (2 ml). NaH (14.1 mg, 0.352 mmol, 60%) was added in one portion, and the mixture was allowed to stir for 10 minutes. Benzyl bromide (0.031 ml, 0.258 mmol) was added and the mixture was allowed to stir for 30 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride, diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to afford 6-(benzyloxy)-4-bromopyrazolo[1,5-a]pyridine.
Reaction SMILES: Cl[C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].[CH3:13][O:14]C1C(F)=C(Br)C=CC=1F>>[CH3:13][O:14][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Reactant: COc1c(F)ccc(Br)c1F
Product: COc1c(F)ccc(C(=O)O)c1F

Procedure:
A procedure analogous to the 3-chloro-2,4-difluorobenzoic acid preparation is used starting from 3-methoxy-2,4-difluoro-bromobenzene.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=2)[N:3]=[CH:2]1.I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]([CH:12]=[O:13])=[CH:10][CH:11]=2)[N:3]=[CH:2]1
Reactant: OCc1ccc(-c2c[nH]cn2)cc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Product: O=Cc1ccc(-c2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.8 %

Procedure:
[4-(1H-Imidazol-4-yl]-phenyl]-methanol (0.21 g, 1.23 mmol) was dissolved in DMSO (12 mL). o-Iodoxybenzoic acid (Frigerio, et al., J. Org. Chem. 1995, 60, 7272) (1.03 g, 3.70 mmol) was added, and the reaction stirred at room temperature for 3.5 hours. The solvent was removed in vacuo, and the residue dissolved in 4:1 CHCl3/iPrOH. The resultant solids were filtered off, and the filtrate washed in turn with 5% Na2SO3/5% NaHCO3 solution, water, and brine, dried (MgSO4) and the solvent removed to give 0.15 g (73%) of 4-(1H-imidazol-4-yl)-benzaldehyde as a yellow solid which was used without further purification: (DMSO-d6) δ 7.84-7.79 (m, 2H), 7.87 (d, 2H, J=8.4 Hz), 7.98 (d, 2H, J=8.2 Hz), 9.94 (s, 1H), 12.30-12.50 (br, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:75]1[CH:80]=[CH:79][C:78](B2OC(C)(C)C(C)(C)O2)=[C:77]([CH3:90])[CH:76]=1)([C:55]1[CH:60]=[CH:59][C:58]([C:61]#[C:62][C:63]2([O:69][Si:70]([CH3:73])([CH3:72])[CH3:71])[CH2:68][CH2:67][S:66][CH2:65][CH2:64]2)=[C:57]([CH3:74])[CH:56]=1)[CH2:53][CH3:54])[CH3:51]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:78]2[CH:79]=[CH:80][C:75]([C:52]([CH2:53][CH3:54])([C:55]3[CH:60]=[CH:59][C:58]([C:61]#[C:62][C:63]4([O:69][Si:70]([CH3:71])([CH3:73])[CH3:72])[CH2:68][CH2:67][S:66][CH2:65][CH2:64]4)=[C:57]([CH3:74])[CH:56]=3)[CH2:50][CH3:51])=[CH:76][C:77]=2[CH3:90])[CH:10]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCSCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCSCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
(5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 58 mg, 0.25 mmol), palladium acetate (3.8 mg, 0.017 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (14 mg, 0.034 mmol), potassium phosphate (108 mg, 0.51 mmol) and water (0.4 mL) were added to a solution of 2-(4-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-thiopyran-4-ylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 136-(4); 100 mg, 0.17 mmol) in toluene (4 mL). The mixture was stirred in a nitrogen atmosphere at 110° C. for two hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:3) to give the title compound (82 mg, 79%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O=[C:7]1[NH:12][N:11]=[C:10]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[CH:9]=[CH:8]1>C(#N)C.O>[Cl:3][C:7]1[N:12]=[N:11][C:10]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOC(=O)c1ccc(=O)[nH]n1
Solvent: CC#N
Solvent: O
Product: CCCCOC(=O)c1ccc(Cl)nn1
Temperature: 0 °C
Yield: 80 %

Procedure:
To a mixture of phosphorus oxychloride (20 ml) and acetonitrile (40 ml) heated at reflux was added a solution of n-butyl 6-oxo-1,6-dihydropyridazine-3-carboxylate (20 g) in acetonitrile (80 ml). The reaction was heated at reflux for 30 minutes, cooled and added to an ice cooled solution of K2C03 (87.8 g) in water (600 ml) with vigorous stirring. The product was filtered off, washed with water and dried at 60° C. to give n-butyl 6-chloropyridazine-3-carboxylate (17.5 g, 80% yield), mpt 110-111° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>ClCCl.O>[CH3:25][N:17]([CH2:16][CH2:15][NH:14][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
2-Nitrobenzenesulfonyl chloride (4.9 g, 22 mmol) was added to a dichloromethane solution (100 ml) of tert-butyl (2-aminoethyl)methylcarbamate (3.5 g, 20 mmol) and triethylamine (3.3 ml, 24 mmol) at 0° C., and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:2→2:3). The purified product was concentrated under reduced pressure to thereby obtain 5.06 g (yield: 70%) of tert-butyl methyl-[2-(2-nitrobenzenesulfonylamino)ethyl]carbamate as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1)#[N:2].Cl.CCOCC>[Pd].CO>[NH2:2][CH2:1][C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CN(C(=O)C(F)(F)F)C2CCCCC2)cn1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NCc1ccc(CN(C(=O)C(F)(F)F)C2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.7 %

Procedure:
Add 6-cyano-3-[N-(cyclohexyl)-N-(2,2,2-trifluoroacetyl)-aminomethyl]-pyridine (1.5 g, 4.8 mmol), 2M hydrogen chloride in ether (7.2 mL, 14.4 mmol) and 10% Pd/C (0.3 g) to methanol (30 mL) in a pressure vessel. Flush the vessel three times with hydrogen and charge to 50 psi with hydrogen. Stir at room temperature for 4 h. Filter the mixture through Whatman® GF/B glass microfiber filter paper, and concentrate in vacuo. Purify the residue by chromatography on silica gel (100 g) eluting with a gradient of DCM to 4:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the title compound as a clear oil (1.6 g, 99%). MS (ES+) m/z: 316 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].[CH3:10][CH2:11]/[CH:12]=[CH:13]/[CH2:14]/[CH:15]=[CH:16]/[CH2:17]/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28].[C:30](=[O:33])([O-])[O-:31].[Na+].[Na+].O>C1C=CC=CC=1>[C:27]([OH:28])(=[O:2])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]/[CH:19]=[CH:18]\[CH2:17]/[CH:16]=[CH:15]\[CH2:14][CH2:13][CH2:12][CH2:11][CH3:10].[C:30]([OH:31])(=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2]
Reactant: O=C([O-])[O-]
Reactant: CC/C=C/C/C=C/C/C=C/CCCCCCCC(=O)Cl
Agent: CCC(CO)(CO)CO
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Temperature: 82.22222222222223 °C

Procedure:
308.02 grams (2.30 moles) of trimethylol propane (MW-134 g/mole) were dissolved in benzene and dried by refluxing and draining the azeotrope. The dry solution was added to 3 liters of diglyme dried with sodium ribbon. The solution was warmed with stirring in a 12 liter flask to 180° F. 682 grams (2.30 moles) of linolenoyl chloride (MW-296.45 g) was added dropwise over a period of three hours. The mixture was stirred overnight at 180° F. An additional 682 grams (2.30 moles) of linolenoyl chloride was added over a period of three hours and again heated at 180° F. overnight. After cooling, an excess of sodium carbonate in a water slurry was added to the reaction mixture to remove the hydrogen chloride. The mixture was then filtered. Approximately 250 ml of hexane were added to approximately 500 ml batches of the product, placed in a separatory funnel of appropriate size and washed three times with 200 ml of deionized water to remove any unreacted TMP and acid along with the diglyme and sodium carbonate. The hexane was removed by rotary evaporation, and the product was stored over molecular sieves.