Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=O)[CH3:3].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:34][CH2:35][C@@H:36]([OH:53])[C@@H:37]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CCN(C(C)C)C(C)C>ClCCl>[OH:53][C@H:36]([CH2:35][NH:34][C:9](=[O:11])[C:8]1[CH:12]=[C:4]([C:2]([CH3:3])=[CH2:1])[CH:5]=[N:6][CH:7]=1)[C@@H:37]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:49])[CH3:50])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Reactant: C=C(C)c1cncc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)c1cncc(C(=O)NC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.5 %

Procedure:
To 5-(prop-1-en-2-yl)nicotinic acid (200 mg, 1.23 mmol) in dichlormethane (10 ml) at rt, EDCI (330 mg, 1.72 mmol) and HOBT (200 mg, 1.48 mmol) were added. After stirring at rt for 10 minutes, tert-butyl (2S,3R)-4-amino-3-hydroxy-1-phenylbutan-2-ylcarbamate (344 mg, 1.23 mmol) was added followed by DIPEA (0.2 ml). After stirring overnight at rt, reaction mixture was worked up as usual and residue was column purified (90% ethylacetate/10% hexanes) to yield 280 mg of tert-butyl (2S,3R)-3-hydroxy-1-phenyl-4-(5-(prop-1-en-2-yl)nicotinamido)butan-2-ylcarbamate, which on stirring with 4N HCl in dioxane for 4 h yields the HCl salt of N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-5-(prop-1-en-2-yl)nicotinamide.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O.C([CH2:22][C:23]([NH:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=[O:29])=[O:24])(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:22]/[C:23]([NH:25][C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([OH:30])=[O:29])=[O:24])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Temperature: 25 °C
Yield: 74.6 %

Procedure:
Piperidine (0.96 mL, 9.7 mmol) was added to a suspension of 3,4-dimethoxybenzaldehyde (1.6 g, 9.7 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (1.9 g, 8.6 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 4 h, then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (5.0 mL) and water (2.0 mL) at 40° C. and the solution was acidified with concentrated HCl. The precipitate was filtered, providing (E)-2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (tranilast) (2.1 g, 74%) as a yellow crystalline solid; mp 208-209° C., lit.2 206° C.; δH (500 MHz, DMSO-d6) 3.79 (s, 3H, OCH3), 3.82 (s, 3H; OCH3), 6.79 (d, J=15.5 Hz, 1H, CH═CHCO), 6.99 (d, J5′,4′=8.5 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=7.9 Hz, 1H, H4), 7.25 (d, J5′,6′=8.5 Hz, 1H, H6′), 7.38 (s, 1H, H2′), 7.56 (d, J=15.5 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=7.9 Hz, 1H, H5), 8.00 (d, J3,4=7.9 Hz, 1H, H3), 8.62 (d, J5,6=7.9 Hz, 1H, H6), 11.30 (s, 1H, NH), 13.61 (br s, 1H, CO2H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.ClC(Cl)(Cl)[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[CH:26]=[N:25][CH:24]=[CH:23]2)=[O:16].C1CCN2C(=NCCC2)CC1>O>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[NH:17][C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=2)=[O:16])[CH:23]=[CH:24][N:25]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(Nc1cccc2ccncc12)C(Cl)(Cl)Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2ccncc12

Procedure:
The title compound was prepared using 4-(trifluoromethyl)benzylamine, the product from Example 57D, DBU and the procedure described in Example 1B. MS (ESI+) m/z 346 (M+H)+; 1H NMR (DMSO-d6) δ 9.58 (s, 1H), 9.10 (s, 1H), 8.49 (d, 1H), 8.12 (d, 1H), 7.81-7.54 (m, 7H), 7.20 (t, 1H), 4.47 (d, 2H); Anal. Calcd for C18H14F3N3O.0.2 H2O: C, 61.96, H 4.16, N 12.04. Found: C, 62.06, H 4.23, N 11.91.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH2:28][CH2:29][NH2:30]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][CH2:29][CH2:28][CH2:27][O:26][CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: COCCCN
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-methoxypropan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79 (quin, J=6.63 Hz, 2H) 2.44 (s, 3H) 3.25 (s, 3H) 3.34 (q, J=6.65 Hz, 2H) 3.40 (t, J=6.19 Hz, 2H) 7.67 (d, J=7.83 Hz, 1H) 7.74 (s, 1H) 7.78 (d, J=6.82 Hz, 1H) 8.18 (br. s., 1H) 8.41 (d, J=6.06 Hz, 2H) 8.71 (t, J=5.31 Hz, 1H) 8.83-9.01 (m, 1H) 13.19 (br. s., 1H). MS m/z [M+H]+ 392.2.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(N(C)C)=O>[F:11][C:4]1[CH:3]=[C:2](/[CH:14]=[CH:13]/[C:12]([O:16][CH3:17])=[O:15])[CH:9]=[C:8]([F:10])[C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1c(F)cc(Br)cc1F
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)/C=C/c1cc(F)c(C=O)c(F)c1
Temperature: 80 °C
Yield: 86.6 %

Procedure:
4-Bromo-2,6-difluorobenzaldehyde (9.99 g, 45.20 mmol) and methyl acrylate (6.14 ml, 67.81 mmol) were taken up in thoroughly degassed DMA (100 ml) and tri-o-tolylphosphine (1.376 g, 4.52 mmol), palladium(II) acetate (0.507 g. 2.26 mmol) and triethylamine (12.60 ml, 90.41 mmol) added. The reaction was stirred and heated to 80° C. for 6 hours. The reaction mixture was cooled and filtered through a layer of celite, and washed with methanol (50 ml). The crude product was pre-absorbed onto silica and purified by suction chromatography eluting with 0-10% diethyl ether/dichloromethane. Fractions containing the desired product were evaporated and triturated with diethyl ether (50 ml) to afford a yellow solid which was triturated with water (50 ml) and dried under high vacuum at 50° C. to afford (E)-methyl 3-(3,5-difluoro-4-formylphenyl)acrylate (8.85 g, 87%) as a yellow solid. 1H NMR (400 MHz, DMSO, 27° C.) δ 3.75 (3H, s), 6.93 (1H, d), 7.52-7.81 (3H, m), 10.18 (1H, s). No mass ion observed in LCMS.
Reaction SMILES: C(OC(C1C(=O)[C:14]2[C:9](=[CH:10][C:11](C(=O)C)=C(F)C=2)[N:8](C2C=CC(F)=CC=2)C=1)=O)C.[CH:28]1([N:31]2[C:40]3[C:35](=[CH:36][C:37]([F:45])=[C:38]([C:42](=O)[CH3:43])[C:39]=3Cl)[C:34](=[O:46])[C:33]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:32]2[S:52][C:53]2C=CC=CC=2)[CH2:30][CH2:29]1>[Ni].[Pd]>[CH:28]1([N:31]2[C:40]3[C:35](=[CH:36][C:37]([F:45])=[C:38]([CH:42]4[CH2:11][CH2:10][CH:9]([NH2:8])[CH2:14][CH2:43]4)[CH:39]=3)[C:34](=[O:46])[C:33]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:32]2[S:52][CH3:53])[CH2:30][CH2:29]1
Reactant: CCOC(=O)c1c(Sc2ccccc2)n(C2CC2)c2c(Cl)c(C(C)=O)c(F)cc2c1=O
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(C(C)=O)c(F)cc2c1=O
Agent: [Ni]
Agent: [Pd]
Product: CCOC(=O)c1c(SC)n(C2CC2)c2cc(C3CCC(N)CC3)c(F)cc2c1=O

Procedure:
In the described fashion as Example 16 (d and e), replacing ethyl 1-ethyl-6-fluoro-7-acetyl-1,4-dihydro-4-oxo-quinoline carboxylate (9) (A=CH, R10 =C2H5, R=C2H5,) with ethyl 1-cyclopropyl-2-methylthio-6-fluoro-7-acetyl-1,4-dihydro-4-oxo-3-carboxylate (13) of Example 40 and also replacing the catalyst Raney nickel in Example 16(e) with palladium on charcoal under a hydrogen atmosphere, one can obtain the ethyl 1-cyclopropyl-2-methylthio-6-fluoro-7-(4 aminocyclohexyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylate (16) (A=CH, R11 =CH3, R10 =C2H5, R=cyclopropyl, Z= ##STR76##
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:30]=[CH:29][S:28][CH:27]=4)[CH2:23][CH2:22][C:21]([C:31]([O:33]C)=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:30]=[CH:29][S:28][CH:27]=4)[CH2:23][CH2:22][C:21]([C:31]([OH:33])=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccsc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccsc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(3-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (373 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 3 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(3-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (297 mg) as yellow crystals.
Reaction SMILES: CC([O:5][C:6]([C@@H:8]([NH:13][C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:9][C:10](O)=[O:11])=[O:7])(C)C.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[BH4-].[Na+].[H-].[Na+].C(Br)C1C=CC=CC=1>O1CCCC1.O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:14]([NH:13][C@H:8]([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][OH:11])([O:16][CH2:17][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:15]
Reactant: CC(C)(C)OC(=O)[C@H](CC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: BrCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N[C@@H](CCO)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.0 mmol of Fmoc Asp-OtBu (42) in 50 mL of dry tetrahydrofuran, kept at −20° C. under nitrogen, is added 1.77 mL (12.7 mmol) of triethyl amine, followed by the slow addition of 1.57 mL (12.0 mmol) of isobutylchloroformate. The mixture is stirred for 30 minutes, and then poured slowly over an ice-cold solution of 3.77 g (99.6 m mol) of sodium borohydride in 10 mL of water, keeping the temperature below 5° C. The reaction is stirred at 0° C. for 15 minutes, and then quenched with 1N hydrochloric acid solution. The reaction mixture is diluted with 100 mL of ethyl acetate, and the layers separated. The organic layer was washed with 2×25 mL of 1N hydrochloric acid solution, 2×25 mL of water, dried over magnesium sulfate and concentrated, and purified by silica gel column chromatography. Purified compound is then dissolved in 30 mL of tetrahydrofuran, and 12 mmol of 60% sodium hydride dispersion in mineral oil is added, followed by 0.2 mmol of tetrabutylammonium iodide and 12 mmol of benzyl bromide, and the mixture is stirred overnight, quenched with 50 mL of saturated aqueous sodium bicarbonate, and extracted with 100 mL of ethyl acetate. The compound is then purified by silica gel column chromatography.
Reaction SMILES: Br[C:2]1[C:3]([CH3:29])=[C:4]([C:21]([OH:28])=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:23]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=1[O:16][C:17]([F:20])([F:19])[F:18])=[O:6].[C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:31].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]([C:4]2[C:3]([CH3:29])=[C:2]([C:35]3[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]=2[OH:28])=[O:6])=[C:9]([O:16][C:17]([F:20])([F:19])[F:18])[CH:10]=1)#[N:15]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1c(Br)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc(C#N)cc1OC(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(C#N)cc2)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc(C#N)cc1OC(F)(F)F
Temperature: 100 °C

Procedure:
To a solution of 3-bromo-5-tert-butyl-N-(2-trifluoromethoxy-4-cyano-phenyl)-6-hydroxy-2-methyl-benzamide (0.141 g, 0.3 mmole) in dioxane (5 ml) under nitrogen, 4-cyanophenylboronic acid (44.0 mg, 0.3 mmole), tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.006 mmole) and sodiumcarbonate (1.05 ml, 2 M solution in water) were added. The reaction mixture was heated at 100° C. for 6 hours. The reaction mixture was evaporated, diluted with ethyl acetate and the organic phase was washed with citric acid solution (10%). The organic phase was dried over sodium sulphate and evaporated. The crude compound was purified by column chromatography.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[NH:10][C:4]=2[NH:5][C:6](=[C:8]=[O:9])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C(O)(C)C.CCCCCC>C(O)CCC>[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:2]1[C:3]2[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[NH:10][C:4]=2[NH:5][C:6](=[C:8]=[O:9])[N:7]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOc1cc2c([nH]1)NC(=C=O)N=C2Cl
Solvent: CCCCO
Solvent: CCCCCC
Solvent: CC(C)O
Product: CCOc1cc2c([nH]1)NC(=C=O)N=C2Nc1cccc(Cl)c1
Temperature: 50 °C

Procedure:
Under a argon atmosphere, 29.0 g (128 mmol) of 4-chloro-6-ethoxy-carbonyl-7H-pyrrolo[2,3-d]pyrimidine and 18.0 ml (171 mmol) of 3-chloroaniline in 430 ml of n-butanol are stirred at 100° C. for 3 h (almost dissolved after≈1 h, then a thick suspension is formed). 400 ml of isopropanol/hexane (1:1) are then added to the reaction mixture cooled to≈50° C., and the product is filtered off and washed with isopropanol and hexane. Stirring in diethyl ether yields 4-(3-chloroanilino)-6-ethoxy-carbonyl-7H-pyrrolo[2,3-d]pyrimidine; 1H-NMR (DMSO-d6) 13.0 and 10.53 (2 sb, 2HN), 8.48 (s, 1H), 8.13 (m, 1H), 7.78 (dm, J=8, 1H), 7.76 (s, 1H), 7.45 (t, J=8, 1H), 7.21 (dm, J=8), 1H), 4.37 (q, J=7, 2H), 1.37 (t, J=7, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][CH2:7]2.Cl[C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([O:21][CH3:22])[N:14]=1.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2([C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([O:21][CH3:22])[N:14]=1)[C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([O:21][CH3:22])[N:14]=1
Reactant: O=C1OCc2cccc(Cl)c21
Reactant: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(OC)nc(C2(c3nc(OC)nc(OC)n3)OC(=O)c3c(Cl)cccc32)n1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
1.48 g of 7-chlorophthalide are dissolved in 80 ml of THF. The solution is cooled to -70° C. and 1.5M IDA in THF (6 ml) is syringed in at -70° C. over 3 min. Stirring is continued for 15 min at -70°, 1.54 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine in 50 ml of THF added dropwise and the mixture is then allowed to warm to -20°. The mixture is again cooled to -70°, and 1 ml of conc. HCl in 10 ml of water is added. The mixture is stirred for 25 min and allowed to warm to RT and the THF is removed by evaporation. The residue is partitioned between CH2Cl2 and water (50 ml each) and the aqueous phase extracted with an additional 30 ml of CH2Cl2. The combined organic phases are washed with 30 ml of water and concentrated to give a yellow gum. This is flash chromatographed on silica gel using 60/40 hexane/ethyl acetate (1000 ml), ethyl acetate (400 ml), 80/20 acetone/methanol (500 ml) (30 fractions×50 ml, 1×200 ml). Fractions 21 and 22 yielded a yellow gum which upon recrystallization from hexane yielded title product m.p. 126°-127° as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].F[C:10]1[CH:11]=[CH:12][C:13]([N+:20]([O-:22])=[O:21])=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][CH:2]1[N:7]([C:10]2[CH:11]=[CH:12][C:13]([N+:20]([O-:22])=[O:21])=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:15]=2)[CH2:6][CH2:5][NH:4][C:3]1=[O:8]
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: CC1NCCNC1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1C(=O)NCCN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 140 °C
Yield: 24.5 %

Procedure:
A mixture of 3-methyl-2-ketopiperazine (200 mg, 1.75 mmol), 5-fluoro-2-nitrobenzo-trifluoride (366 mg, 1.75 mmol), N,N-diisopropylethylamine and N,N-dimethylformamide (1 mL) was heated at 140° C. for 10 min under microwave irradiation, then partitioned between sat. aq. ammonium chloride solution and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane/EtOAc 4:1) produced the title compound (130 mg, 24%). Yellow solid, MS: 304.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[CH2:6]=[O:7]>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH2:4][CH2:3][O:2][CH3:1]
Reactant: C=O
Reactant: COCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COCCOCOCCOC
Yield: 71.4 %

Procedure:
1045 g of 2-methoxyethanol (Mr =76,1), 194 g of paraformaldehyde (Mr =30.03 based on formaldehyde) and 16 g of p-toluenesulfonic acid (Mr =172.2) are reacted for 2 hours at 90° C. The water of reaction is then removed by distillation. The reaction mixture is distilled under reduced pressure (c. 20 mbar), affording 758 g of bis(2-methoxyethoxy)methane (Mr =164.21) in c. 99% purity, yield: 67% of theory. The remainder (33%) consists almost completely of the educt, which can be recycled, so that total yields of over 97% result.
Reaction SMILES: [OH:1][C:2]1([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](C#CC3C=CC(C(OCC)=O)=CC=3)[CH:5]=[CH:4][C:3]1=2.CC1(C)C2C=CC([C:44]#[C:45][C:46]3[CH:56]=[CH:55][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:48][CH:47]=3)=CC=2C(=O)CC1>>[OH:1][C:2]1([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[CH:6][C:5]([C:44]#[C:45][C:46]3[CH:56]=[CH:55][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:48][CH:47]=3)=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Reactant: CCOC(=O)CC1(O)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC)cc3)ccc21
Product: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate (Compound 113), 1.00 g (2.88 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound (light yellow solid) using 1.00 g (15.30 mmol) of zinc, 0.639 ml (5.76 mmol) of ethyl bromoacetate and 70 ml of dry benzene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14](S(C4C=CC=CC=4)(=O)=O)[C:15]([C:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: [H][H]
Reactant: COc1ccc(F)cc1-c1ccnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCN(C(=O)OC(C)(C)C)CC3)cc12
Temperature: 90 °C

Procedure:
A solution of Example 87C (2.35 g, 4.17 mmol) in ethanol (40 mL) was added to 20% palladium hydroxide on carbon (wet, 2.35 g, 1.707 mmol) in a stainless steel pressure bottle and was stirred at 50° C. for several days at 50 psi hydrogen. The mixture was filtered through a nylon membrane and concentrated. The residue was dissolved in 30 mL 1,4-dioxane and treated with 2 mL 20% sodium hydroxide. The mixture was heated at 90° C. for 4 hours and was concentrated. The residue was treated with water and extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate, filtered, concentrated, and purified using an ISCO Companion flash system on silica eluting with dichloromethane/ethyl acetate (5:5 to 4:6) to afford the title compound. MS (ESI+) m/z 425.9 (M+H)+.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:17][Mg]Br.O>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[OH:1][CH:2]([CH3:17])[CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 250 mg of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate in 5 mL of THF was added 1.2 mL of 1.4M methyl magnesium bromide in toluene-THF, followed by stirring at room temperature for 2 hours. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1] to obtain 236 mg of tert-butyl 4-(2-hydroxypropyl)piperidine-1-carboxylate as a colorless oily substance.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([NH2:27])[C:19]=2[N:18]=[C:17]1[CH2:28][O:29][CH2:30][CH3:31]>>[NH2:27][C:20]1[C:19]2[N:18]=[C:17]([CH2:28][O:29][CH2:30][CH3:31])[N:16]([CH2:15][CH2:14][CH2:13][NH:12][C:3](=[O:4])[N:2]([CH3:1])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:24]=2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCN
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCNC(=O)N(C)c1ccccc1

Procedure:
Using the method of Examples 94-105, N-methyl-N-phenylcarbamoyl chloride was reacted with 1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 411.2513.