Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:26].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1>>[ClH:26].[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:39][CH2:38][N:37]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]3[CH:11]=[CH:10][C:9]4[O:8][C:7]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[CH:6][C:5](=[O:18])[C:4]=4[CH:3]=3)[CH2:36][CH2:35]2)=[CH:32][CH:33]=1
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: ClCCCCCCBr
Product: Cl
Product: O=c1cc(-c2ccccc2)oc2ccc(OCCCCCCN3CCN(c4ccc(Cl)cc4)CC3)cc12

Procedure:
The compound was prepared by the method of Example 3 from 6-hydroxyflavone, 1-bromo-6-chlorohexane, and 4-(4-chlorophenyl)piperazine: mp 227°-229° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:29](=[O:31])[CH3:30])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27]Br)=[CH:11][CH:12]=2)[CH:7]=1.[OH:33][C:34]1[C:39]([CH2:40][CH2:41][CH3:42])=[C:38]([OH:43])[CH:37]=[CH:36][C:35]=1[C:44](=[O:46])[CH3:45].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:29](=[O:31])[CH3:30])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:43][C:38]3[CH:37]=[CH:36][C:35]([C:44](=[O:46])[CH3:45])=[C:34]([OH:33])[C:39]=3[CH2:40][CH2:41][CH3:42])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)COc1ccc2ccc(OCCOCCOCCOCCBr)c(C(C)=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCOCCOCCOCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 81.9 %

Procedure:
A mixture of 3 g of [[8-acetyl-7-[2-[2-[2-[2-bromoethoxy]ethoxy]ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester, 1.36 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone and 1.2 g of anhydrous potassium carbonate in 60 ml of anhydrous acetone and 20 ml of anhydrous dimethylformamide was stirred at reflux for 18 hours. The mixture was filtered and filtrate was concentrated in vacuo to an oil which was purified by high pressure liquid chromatography (35% ethyl acetate-toluene) to yield 3 g (82%) of [[8-acetyl-7-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[F:22][C:23]([F:29])([F:28])[S:24](Cl)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:22][C:23]([F:29])([F:28])[S:24]([N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:14][CH2:13]1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 150 ml round-bottomed flask equipped with a magnetic stirrer is charged under argon with 2 g of 4-N-boc-aminopiperidine in 35 ml of DCM, 82 mg of 4-dimethylaminopyridine (DMAP) and 1.86 ml of triethylamine. After cooling to 0° C. using an ice bath, 1.6 ml of trifluoromethanesulphonyl chloride are added dropwise. The mixture is stirred at 0° C. for 30 min and then at RT for 1 h. It is poured into 100 ml of saturated aqueous sodium bicarbonate solution. It is extracted with AcOEt, washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated to dryness under RP. Chromatography on silica gel (15-40 μm), eluting with a mixture of DCM and methanol (98/02 by vol.), gives 1.5 g of 1,1-dimethylethyl (1-trifluoromethanesulphonylpiperidin-4-yl)carbamate (cream solid). MS (E/I): m/z=232 (M+).
Reaction SMILES: [OH-].[Na+].CC(O)C.[OH:7][C:8]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[CH:29][C:9]=1[C:10]([NH:12][C:13]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:14]=1[C:15]([O:17]C)=[O:16])=[O:11].[ClH:42]>O>[ClH:42].[OH:7][C:8]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]2[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]2)=[CH:29][C:9]=1[C:10]([NH:12][C:13]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][C:14]=1[C:15]([OH:17])=[O:16])=[O:11]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCC2CCN(C)CC2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CN1CCC(COc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (0.37 mL) was added to a 2-propanol (1.0 mL) suspension of the obtained methyl 2-(2-hydroxy-5-((1-methylpiperidin-4-yl)methoxy)benzamido)-4-phenylbenzoate (0.070 g), followed by stirring at 50° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then water was added thereto. After adjusting the pH to 6.0 with 1 mol/L hydrochloric acid, the solid substance was collected by filtration. Ethyl acetate (2.0 mL) and a 4 mol/L hydrogen chloride dioxane solution (0.20 mL) were added to the obtained solid substance, followed by stirring at room temperature for 2 hours. The solid substance was collected from the reaction mixture by filtration to obtain 0.058 g of 2-(2-hydroxy-5-(1-methylpiperidin-4-ylmethoxy)benzamido)-4-phenylbenzoic acid hydrochloride as a light yellow solid.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:19]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:20][C:21](O)=[O:22].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:21](=[O:22])[CH2:20][C:19]([O:25][CH2:26][CH3:27])=[O:24])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: CCOC(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Yield: 69 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (400 mg), ethyl hydrogen malonate (225 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (326 mg), 1-hydroxy-1H-benzotriazole monohydrate (260 mg), triethylamine (0.697 mL), and N,N-dimethylformamide (5 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 90:10-70:30 hexane/ethyl acetate) to provide the title compound (312 mg, 69%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@H:5]([C:16]([OH:18])=[O:17])[NH:4]1.C(N(CC)CC)C.[C:26](=[S:28])=[S:27].[CH3:29]I>CO>[OH:1][CH2:2][C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@H:5]([C:16]([OH:18])=[O:17])[N:4]1[C:26]([S:28][CH3:29])=[S:27]
Reactant: CI
Reactant: S=C=S
Reactant: O=C(O)[C@H]1Cc2c([nH]c3ccccc23)[C@H](CO)N1
Solvent: CCN(CC)CC
Solvent: CO
Product: CSC(=S)N1[C@@H](C(=O)O)Cc2c([nH]c3ccccc23)[C@@H]1CO

Procedure:
In the same manner as described in Example 43, (1RS,3SR)-trans-1-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (1.48 g), triethylamine (1.68 ml), carbon disulfide (0.73 ml), methyl iodide (0.75 ml) and 80% methanol (20 ml) are reacted and treated. The product is crystallized from aqueous ethanol to give the title compound (0.68 g), m.p. 187°-188° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[F:8].[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20](O)=[O:21])=[CH:19][N:14]2[CH:13]=1>>[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20]([NH:10][CH2:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)=[O:21])=[CH:19][N:14]2[CH:13]=1
Reactant: NCc1ccc(F)c(Cl)c1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Product: O=C(NCc1ccc(F)c(Cl)c1)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (3-chloro-4-fluorophenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:22][N:23](C)[C:24](=O)[O:25][C:26]([CH3:29])(C)C)[C:9]=2[F:32])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:33]([O:36]CC)(=[O:35])[CH3:34].Cl.C([OH:42])C>>[C:26]([OH:25])(=[O:42])/[CH:29]=[CH:34]/[C:33]([OH:36])=[O:35].[Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:22][NH:23][CH3:24])[C:9]=2[F:32])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCO
Reactant: CN(Cc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CNCc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2Cl)c1F
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (439 mg) in ethanol (4 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=1:1) to give the title compound as a free base (267 mg). To a solution of the obtained free base (264 mg) in ethyl acetate (2 mL) was added a solution of fumaric acid (81.1 mg) in ethanol (2 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol-water to give the title compound as a white solid (yield 225 mg, 49%).
Reaction SMILES: [N+:1]([C:4]1[C:14]2[C:15]3[C:7]([CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.C>O1CCCC1.C(O)(=O)C.C(Cl)Cl.[Pd]>[NH2:1][C:4]1[C:14]2[C:15]3[C:7]([CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c3c(cccc13)CC2
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1ccc2c3c(cccc13)CC2
Reaction time: 2 h

Procedure:
40 gms (Aldrich lot #CY 02301 HX, containing 15% of the 3-nitro isomer) of 5-nitroacenaphthene was dissolved in a mixture of tetrahydrofuran (150 ml) and acetic acid (25 ml.). To this solution was added 1.0 of 10% Pd/C and the mixture hydrogenated (40 psi) at room temperature. After 2 hours, the mixture was filtered through a bed of celite and the filtrate concentrated in vacuo to give a mixture of a solid which darkened (to purple) considerably on exposure to air. This material was redissolved in methylene chloride and decolorized with activated charcoal and then the product recrystallized from a mixture of cyclohexane:ethyl acetate (3:1) to give 8.3 g of clean material--only the major 5-amino isomer being present by TLC. This material was used as is directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([NH:18]CC4C=CC(OC)=CC=4OC)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>CO.ClCCl>[NH2:18][C:15]1[CH:16]=[CH:17][C:10]2[CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:12](=[O:13])[C:11]=2[CH:14]=1
Reactant: COc1ccc(CNc2ccc3ccc4ncc(Cl)cc4c(=O)c3c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.05 g, 3.30 mmol), Pd2(dba)3 (8 mg, 0.00825 mmol), BINAP (15 mg, 0.0248 mmol) and benzophenone imine (0.662 mL, 3.95 mmol) were combined in a dry flask. The flask was charged with 40 mL of dry toluene, followed by sodium tert-butoxide (0.444 g, 4.62 mmol). Argon was bubbled through the solution for 5 minutes. The reaction solution was heated to 110° C. and stirred under argon. After 2.5 hours, the reaction was concentrated, 20 mL of THF and 1 mL of 6N hydrochloric acid were added and the resulting solution was stirred. After 2 hours, the solution was poured into 300 mL of ethyl acetate, 100 mL of saturated sodium bicarbonate and 200 μL of water. The organic layers were separated, dried with magnesium sulfate, filtered, concentrated, and purified by flash column chromatography (0-30% ethyl acetate/hexanes gradient) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.77 (d, 1H); 8.55 (d, 1H); 7.58 (d, 1H); 7.44 (d, 1H); 7.18 (d, 1H); 7.14 (d, 1H); 7.01 (dd, 1H); 4.15 (s, 2H). LRMS (APCI) calculated for C14H10ClN2O [M+H]+, 257.0; found 257.1. Method B: 3-chloro-7-[(2,4-dimethoxybenzyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.1 g, 2.7 mmol) was dissolved in 8 mL methanol and 30 mL dichloromethane. Then 10 mL of trifluoroacetic acid was added and the solution was stirred at ambient temperature. After 1 hour, reaction was concentrated, dissolved in 500 mL of ethyl acetate and washed with 200 mL saturated sodium bicarbonate. The organic layer was separated, dried with magnesium sulfate, filtered, and purified by flash column chromatography (0-10% methanol/dichloromethane gradient) and reverse phase HPLC (20-100% acetonitrile/water gradient, 0.1% trifluoroacetic acid modifier) to afford title compound. LRMS (APCI) calculated for C14H10ClN2O [M+H]+, 257.0; found 257.1.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[CH3:16][C:17]1([CH3:27])[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([OH:26])[C:19]=2[O:18]1.C[O:29][C:30](=[O:39])[CH:31](Br)[CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH:33]1([CH2:32][CH:31]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:26][C:25]3[C:19]4[O:18][C:17]([CH3:27])([CH3:16])[CH2:21][C:20]=4[CH:22]=[CH:23][CH:24]=3)[CH:6]=[N:5]2)[C:30]([OH:29])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: CC1(C)Cc2cccc(Oc3cnn(C(CC4CCCC4)C(=O)O)c(=O)c3)c2O1

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,2-dimethyl-2,3-dihydro-benzofuran-7-ol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid as a white solid (14 g, 91% for the final step); LC-MS: tR=3.73 min, 399 [M+H]+. HPLC: tR=6.52 min, 98.99% at 214 nm, 99.32% at 254 nm. 1H NMR (300 MHz, CD3OD): δ 7.99 (s, 1H), 7.17-6.89 (m, 3H), 5.87 (s, 1H), 5.52-5.48 (m, 1H), 3.12 (s, 2H), 2.40-2.32 (m, 1H), 2.13-2.10 (m, 1H), 1.81-1.52 (m, 7H), 1.45 (s, 6H), 1.20-1.14 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.O>N1C=CC=CC=1.O1CCCC1>[F:10][C:11]([F:21])([F:22])[C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:17])=[CH:14][CH:13]=1
Reactant: COc1ccccc1N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1NC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1.7 h
Yield: 98.1 %

Procedure:
To a solution of 20.8 g of o-anisidine in 140 ml of pyridine was added dropwise a solution of 35.2 g of p-trifluoromethyl benzoyl chloride in 30 ml of tetrahydrofuran at 50° to 10° C. After stirring at room temperature for 1.7 hours, the reaction mixture was poured into 1.6 liters of water. The precipitate was collected by filtration, washed with water, and dried to give 48.9 g of 4- trifluoromethyl -2'-methoxybenzanilide.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[CH3:12][CH:13]([NH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:28]([S:29][C:30]2[CH:35]=[C:34]3[O:36][CH2:37][O:38][C:33]3=[CH:32][C:31]=2I)=[N:27][C:21]2[C:22]([NH2:26])=[N:23][CH:24]=[N:25][C:20]1=2)[CH3:14].C([O-])(O)=O.[Na+].CN(C=O)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.O>[NH2:26][C:22]1[N:23]=[CH:24][N:25]=[C:20]2[C:21]=1[N:27]=[C:28]([S:29][C:30]1[C:31]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[CH:32][C:33]3[O:38][CH2:37][O:36][C:34]=3[CH:35]=1)[N:19]2[CH2:18][CH2:17][CH2:16][NH:15][CH:13]([CH3:12])[CH3:14]
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
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: CN(C)C=O
Solvent: O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2ccc(C=O)cc2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C
Yield: 65.5 %

Procedure:
4-Formylphenylboronic acid (13 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH—NH3 (7N), 2:2:1:0.5) to give 18.8 mg (66%) of DZ3-50. 1H NMR (500 MHz, MeOH-d4) δ 10.01 (s, 1H), 8.15 (s, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.14 (s, 1H), 6.93 (s, 1H), 6.13 (s, 2H), 4.05 (t, J=6.8 Hz, 2H), 2.99 (septet, J=6.4 Hz, 1H), 2.62 (t, J=6.9 Hz, 2H), 1.99 (m, 2H), 1.24 (d, J=6.4 Hz, 6H); 13C NMR (125 MHz, MeOH-d4) δ 192.3, 154.1, 151.9, 151.0, 149.8, 148.8, 148.5, 146.4, 139.5, 135.3, 130.0, 129.4, 119.0, 117.7, 115.0, 110.8, 102.4, 49.9, 42.2, 40.3, 27.4, 20.2; HRMS (ESI) m/z [M+H]+ calcd. for C25H27N6O3S, 491.1865; found. 491.1877; HPLC: method A Rt=6.23, method B Rt=6.83.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:31][C:30]5[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=5[C:28]([F:27])([F:37])[F:38])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3ccccc3C(F)(F)F)C2=O)CC1
Yield: 93 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2-(trifluoromethyl)benzyl bromide, to give the desired product as a light yellow foam (93%).
Reaction SMILES: [CH:1]1([C:4]([OH:32])([CH3:31])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][C:12]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)=[C:11](C3C=CC(Cl)=CC=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.C1(C(O)(C)CNC(C2C(C(F)(F)F)=NC(Br)=C([C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([Cl:58])[CH:53]=3)N=2)=O)CC1>>[CH:1]1([C:4]([OH:32])([CH3:31])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:16])[F:17])=[N:13][C:12]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)=[C:11]([C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([Cl:58])[CH:53]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CC(O)(CNC(=O)c1nc(-c2cccc(Cl)c2)c(Br)nc1C(F)(F)F)C1CC1
Reactant: CC(O)(CNC(=O)c1nc(-c2ccc(Cl)cc2)c(OCC2CC2)nc1C(F)(F)F)C1CC1
Product: CC(O)(CNC(=O)c1nc(-c2cccc(Cl)c2)c(OCC2CC2)nc1C(F)(F)F)C1CC1

Procedure:
In analogy to example 3 (6-(4-chloro-phenyl)-5-cyclopropylmethoxy-3-trifluoromethyl-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide) the title compound was prepared by substituting 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide with 5-bromo-6-(3-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH+:20][CH2:21]C>C(#N)C>[Br-:20].[OH:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[N:10]([CH3:21])[CH2:9][NH+:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]=2)=[CH:18][CH:17]=1
Reactant: Oc1ccc(-c2cn(Cc3ccccc3)cn2)cc1
Reactant: CC[BrH+]
Solvent: CC#N
Product: CN1C[NH+](Cc2ccccc2)C=C1c1ccc(O)cc1
Product: [Br-]
Reaction time: 2 h

Procedure:
Through a stirred and refluxing mixture of 5.5 parts of 4-[1-(phenylmethyl)-1H-imidazol-4-yl]phenol and 120 parts of acetonitrile, gaseous bromomoethane is bubbled till the solution is clear. Stirring at reflux is continued for 2 hours while gaseous bromomethane is still introduced. The solvent is evaporated and the solid residue is triturated in 2-propanone. The product is filtered off and dried, yielding 7.5 parts of 4-(4-hydroxyphenyl)-3-methyl-1-(phenylmethyl)-1H-imidazolium bromide.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:4]=C([CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1)C(N(C)C)=O.CO.C[CH2:20][O:21][C:22]([CH3:24])=[O:23].C([O-])(O)=O.[Na+]>OS(O)(=O)=O.O>[CH3:1][N:2]([CH3:16])[C:3]1[CH:4]=[C:24]([CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1)[C:22]([O:21][CH3:20])=[O:23]
Reactant: CCOC(C)=O
Reactant: CN(C)C(=O)c1cc(CO)nc(N(C)C)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(CO)nc(N(C)C)c1
Temperature: 135 °C
Reaction time: 12.5 h
Yield: 65 %

Procedure:
A mixture of 167 mg of 2-(dimethylamino)-6-(hydroxymethyl)-N,N-dimethylisonicotinamide in 2 mL of H2SO4 and 1.2 mL of H2O was stirred at 135° C. for 12.5 h. The temperature was decreased to 95° C., methanol (5 mL) was added, and the solution was heated for 1 h. The solution was added to ice with H2O and EtOAc, and solid NaHCO3 and sat. NaHCO3 solution were added to pH=8. The aqueous layer was extracted with EtOAc (4×), and the combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (30% EtOAc/hexanes) provided 102 mg of methyl 2-(dimethylamino)-6-(hydroxymethyl)isonicotinate as a yellow solid in 65% yield.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:23])[NH:18][CH2:19][CH2:20][CH2:21][NH2:22])([CH3:15])(C)C.[CH3:24][C:25](C)=O>>[C:1]([NH:9][C:10](=[S:11])[NH:22][CH2:21][CH2:20][CH2:19][NH:18][C:17](=[O:23])[O:16][CH2:12][CH2:15][CH2:24][CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CC(C)=O
Product: CCCCOC(=O)NCCCNC(=S)NC(=O)c1ccccc1
Temperature: 60 °C
Yield: 43 %

Procedure:
Prepared according to the procedure described by Jubian at al. Angew. Chem, 1995, 107, 1343 and Rasmussen et al. Synthesis, 1988, 456. To a solution of benzoyl isothiocyanate (0.93 g, 5.70 mmol) in acetone (10 mL) was added tert-butyl(3-aminopropyl)carbamate (0.95 g, 5.45 mmol). After heating at 60° C. for 2.5 h, the reaction mixture was concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-heptane, 0-40%), affording the title compound (0.83 g, 43%). LCMS: Rt=0.93 min, m/z=338.0 (M+1) Method 2m_acidic.