Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10](O)=[O:11])=[O:6])[CH2:2][CH3:3].C([N:27](CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[O:17]1[CH:18]=[CH:19][N:20]=[C:16]1[C:14]1[CH:15]=[C:7]([C:5]([N:4]([CH2:21][CH2:22][CH3:23])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:8]=[C:9]([CH:13]=1)[C:10]([NH2:27])=[O:11]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 148.5 %

Procedure:
A solution of 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoic acid 38 (120 mg, 0.38 mmol) in methylene chloride (3.8 mL) containing N,N-diisopropylethylamine (132 μL, 0.76 mmol) and HBTU (151 mg, 0.40 mmol) was stirred at room temperature for 0.5 h. To the above solution was added a solution of the orange oil from step 7 (207 mg, 0.57 mmol) in methylene chloride (3.8 mL) containing N,N-diisopropylethylamine (132 μL, 0.76 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then diluted with additional methylene chloride and washed with saturated sodium bicarbonate and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield an oily residue. Purification by flash column chromatography (silica, 90:10 methylene chloride/methanol) gave N1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[({2-(dimethylamino)methyl]pyridin-4-yl}methyl)amino]-2-hydroxypropyl}-5-(1,3-oxazol-2-yl)-N3,N3-dipropylisophthalamide (178 mg): mp 63-66° C.; ESI MS m/z 663 [M+H]+.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[CH:18]1([CH:23]=O)[CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1>[CH:18]1([CH:23]=[CH:3][C:1]#[N:2])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=CC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=CC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A solution of diethyl cyanomethylphosphonate (7, 742.5 g, 4.2 mol, 1.1 equiv) in dry THF (5.75 L) was stirred under nitrogen on an ice-water-methanol bath and a solution of 1 M potassium tert-butoxide in THF (4 L, 4.0 mol, 1.05 equiv) was added at such a rate as to keep the temperature below 0° C. After addition of 1 M potassium tert-butoxide in THF was complete, the stirring was continued on the cold bath for 1 h and a solution of cyclopentanecarbaldehyde (6, 374 g, 3.81 mol) in dry THF (290 mL) was added at such a rate as to maintain the temperature below 0° C. The cold bath was removed, and the reaction mixture was gradually warmed to room temperature and stirred at room temperature for overnight. When the reaction was deemed complete, the reaction mixture was partitioned between methyl tent-butyl ether (MTBE, 14 L), water (10 L) and brine (6 L). The two layers were separated, and the combined organic phase was washed with brine (6 L). The aqueous phase was extracted with MTBE (10 L) and washed with brine (6 L). The combined organic extracts were concentrated under reduced pressure and the residue was distilled (65-78° C./6 torr) to afford 3-cyclopentylacrylonitrile (8, 437.8 g, 461.7 g theoretical, 94.8% yield) as a colorless oil, which was found to be a mixture of E- and Z-isomer. For 8: 1H NMR (DMSO-d6, 400 MHz, for Z-isomer) δ ppm 6.58 (t, 1H, J=10.6 Hz), 5.55 (dd, 1H, J=10.8, 0.59 Hz), 2.85 (m, 1H), 1.9-1.46 (m, 6H), 1.34 (m, 2H) and (for E-isomer) δ ppm 6.83 (q, 1H, J=8.3 Hz), 5.66 (dd, 1H, J=16.5, 1.4 Hz), 2.60 (m, 1H), 1.9-1.46 (m, 6H), 1.34 (m, 2H); 13C NMR (DMSO-d6, 100 MHz, for Z-isomer) δ ppm 159.8, 116.6, 97.7, 42.3, 32.3, 25.1 and (for E-isomer) δ ppm 160.4, 118.1, 97.9, 43.2, 31.5, 24.8; C8H11N (MW, 121.18), GCMS (EI) m/e 120 (M+−H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:14]=1[F:23])=[CH:6][C:7]([O:9]CC)=O)[CH3:2]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH3:22][O:21][C:19]([C:17]1[C:18]2[C:7](=[O:9])[CH:6]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:24])[NH:12][C:13]=2[C:14]([F:23])=[CH:15][CH:16]=1)=[O:20]
Reactant: CCOC(=O)C=C(Nc1cc(C(=O)OC)ccc1F)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cc(=O)c2c(C(=O)OC)ccc(F)c2[nH]1
Temperature: 300 °C
Reaction time: 1 h

Procedure:
A suspension of 33 (25.0 g, 73.7 mmol) in Dowtherm A (200 mL) was heated to 300° C. over the course of 30 minutes and then stirred at 300° C. for 1 h. The reaction solution was cooled to room temperature and purified by flash chromatography (Hexanes to EtOAc) to afford a white solid (34, 12.1 g, 56.1%). 1H NMR (CDCl3, 300 MHz) δ 9.19 (br s, 1H), 7.42 (t, J=8.2, 1H), 7.21-7.25 (m, 1H), 6.92 (s, 1H), 4.51 (q, J=7.1, 2H), 3.99 (s, 3H), 1.46 (t, J=7.1, 3H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[C:8](Cl)=[C:7]([C:13]#[N:14])[CH2:6]1)([OH:3])=[O:2].N(C(C)(C)C#N)=NC(C)(C)C#N.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[CH:8]=[C:7]([C:13]#[N:14])[CH2:6]1)([OH:3])=[O:2]
Reactant: CC1CN(CC(=O)O)CC(C#N)=C1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC1C=C(C#N)CN(CC(=O)O)C1

Procedure:
To a solution of 43 (24 g, 0.0105 mol) in toluene (400 ml) was added azobisisobutyronitrile (6 g) and tri-n-butyltin hydride (90 g). The mixture was refluxed overnight and then evaporated in vacuo. Elution from a column of silica gel with ethyl acetate - heptane (1:2) gave the title compound as an oil. Yield: 10.4 g (0.0538 mol, 51%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][N:33]3COCC[Si](C)(C)C)=[CH:29][CH:28]=2)[CH:23]=[C:24]([Cl:26])[CH:25]=1.C(OCC)(=O)C>O1CCCC1>[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][NH:33]3)=[CH:29][CH:28]=2)[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3cc(Cl)cc(Cl)c3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3cc(Cl)cc(Cl)c3)ccc12
Temperature: 65 °C

Procedure:
11.2 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1 g of N-[6-(3,5-dichlorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 20 cm3 of tetrahydrofuran, the reaction medium is then heated at about 65° C. for 18 hours and the heating is stopped to add 75 cm3 of ethyl acetate. The organic phase is washed with 2×50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 50° C.), 290 mg of N-[6-(3,5-dichlorophenyl)-1H-indazol-3-yl]butanamide are obtained in the form of a white product.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH2:14])=[S:13])[CH:8]=[CH:9][CH:10]=1)(=O)C.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O>C(O)C>[C:19]1([C:17]2[N:14]=[C:12]([NH:11][C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[NH2:4])[S:13][CH:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(=O)Nc1cccc(NC(N)=S)c1
Solvent: CCO
Product: Nc1cccc(Nc2nc(-c3ccccc3)cs2)c1
Yield: 82 %

Procedure:
A mixture of N-(3-acetylaminophenyl)thiourea (0.84 g) and 2-bromoacetophenone (0.84 g) in ethanol (10 ml) was refluxed for 15 minutes. After evaporation of the solvent, 3N hydrochloric acid was added thereto and the mixture was refluxed for 30 minutes. The mixture was made basic with sodium bicarbonate and extracted with ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from ethanol to give 3-(4-phenylthiazol-2-yl)aminoaniline (0.88 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[C:39]5[CH:38]=[C:37]6[C:40]([CH3:48])([CH3:47])[C:41]7[C:46]([C:36]6=[CH:35][C:34]=5[C:33]5[C:28]4=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:45][CH:44]=[CH:43][CH:42]=7)=[CH:23][CH:22]=3)=[CH:17][CH:16]=1)[C:10]1[CH:9]=[C:8]3[C:49]([CH3:57])([CH3:56])[C:50]4[C:55]([C:7]3=[CH:6][C:5]2=1)=[CH:54][CH:53]=[CH:52][CH:51]=4.[B:58]1(B2OC(C)(C)C(C)(C)O2)[O:62][C:61]([CH3:64])([CH3:63])[C:60]([CH3:66])([CH3:65])[O:59]1.C([O-])(=O)C.[K+].ClCCl>O1CCOCC1>[CH3:65][C:60]1([CH3:66])[C:61]([CH3:64])([CH3:63])[O:62][B:58]([C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[C:39]6[CH:38]=[C:37]7[C:40]([CH3:48])([CH3:47])[C:41]8[C:46]([C:36]7=[CH:35][C:34]=6[C:33]6[C:28]5=[CH:29][CH:30]=[CH:31][CH:32]=6)=[CH:45][CH:44]=[CH:43][CH:42]=8)=[CH:23][CH:22]=4)=[CH:17][CH:16]=2)[C:10]2[CH:9]=[C:8]4[C:49]([CH3:57])([CH3:56])[C:50]5[C:55]([C:7]4=[CH:6][C:5]3=2)=[CH:54][CH:53]=[CH:52][CH:51]=5)[O:59]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccc(-n6c7ccc(Br)cc7c7cc8c(cc76)C(C)(C)c6ccccc6-8)cc5)cc4)c3cc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccc(-n6c7ccc(B8OC(C)(C)C(C)(C)O8)cc7c7cc8c(cc76)C(C)(C)c6ccccc6-8)cc5)cc4)c3cc21

Procedure:
7.1 g (9.0 mmol) of 4-(7-bromo-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluoren-10-yl)-4′-(12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluoren-10-yl)biphenyl, 2.5 g (9.85 mmol) of bis(pinacolato)diborane and 2.6 g (26 mmol) of potassium acetate are suspended in 500 ml of dioxane. 0.22 g (0.27 mmol) of 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloride complex with dichloromethane is added to this suspension. The reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, washed three times with 150 ml of water and subsequently evaporated to dryness. The residue is recrystallised from toluene. The yield is 6.8 g (8 mmol, 90%).
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:19][C:20]1[S:24][C:23]([C:25](OCC)=[O:26])=[CH:22][CH:21]=1.Cl>C1COCC1.C1(C)C=CC=CC=1>[C:5]([O:4][C:1](=[O:3])[CH2:2][C:25]([C:23]1[S:24][C:20]([Cl:19])=[CH:21][CH:22]=1)=[O:26])([CH3:8])([CH3:7])[CH3:6]
Reactant: CCOC(=O)c1ccc(Cl)s1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)c1ccc(Cl)s1
Temperature: 0 °C
Yield: 68 %

Procedure:
A 0.25M THF solution of tert-butyl acetate (2.90 g, 25 mmol) is added dropwise to a cold (−78° C.) solution of potassium bis(trimethylsilyl)amide (100 ml of a 0.5M toluene solution) and ethyl 5-chlorothiophene-2-carboxylate (Lancaster)(4.77 g, 25 mmol) in 50 ml of THF. The reaction is allowed to warm to 0° C. over one hour. After stirring an additional hour at 0° C., the reaction is poured into 100 ml of a 1M HCl solution. The organic layer is extracted with brine and evaporated in vacuo. The crude residue is purified by flash column chromatography eluting with 5% ethyl acetate/hexane to provide the product (4.54 g, 17 mmol) as an oil. 1H NMR (CDCl3, 300 MHz) δ7,53 (d, 1H), 6.98 (d, 1H), 3.78 (3, 2H), 1.50 (s, 9H).
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[CH:17]=[C:16](I)[C:12]2[O:13][CH2:14][O:15][C:11]=2[C:10]=1[NH2:19].[CH3:20][N:21]([CH3:29])[C:22](=[O:28])[CH2:23][O:24][CH2:25][C:26]#[CH:27]>C(OCC)(=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>[NH2:19][C:10]1[C:11]2[O:15][CH2:14][O:13][C:12]=2[C:16]([C:27]#[C:26][CH2:25][O:24][CH2:23][C:22]([N:21]([CH3:29])[CH3:20])=[O:28])=[CH:17][C:9]=1[Cl:8]
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Reactant: C#CCOCC(=O)N(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CN(C)C(=O)COCC#Cc1cc(Cl)c(N)c2c1OCO2
Temperature: -20 °C
Yield: 81.9 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (0.236 g), cuprous iodide (0.96 g) and diisopropylamine (0.47 ml) were added to a stirred solution of 5-chloro-7-iodo-1,3-benzodioxol-4-amine (0.500 g) and N,N-dimethyl-2-(prop-2-yn-1-yloxy)acetamide (0.474 g) in ethyl acetate (8 ml) cooled to −20° C. under a nitrogen atmosphere; the resultant mixture was stirred for 4 hr at ambient temperature. The reaction mixture was filtered through Celite, ethyl acetate (12 ml) was then added and the resultant solution washed with saturated aqueous sodium bicarbonate (20 ml). The aqueous layer was re-extracted with ethyl acetate (20 ml). The combined organic extracts were washed with brine (20 ml), dried over sodium sulphate and then evaporated. The residue was purified by column chromatography on silica using ethyl acetate as eluent. There was thus obtained the title compound as a solid (0.428 g). NMR Spectrum: (CDCl3) 2.96 (s, 3H), 3.02 (s, 3H), 4.06 (s, 2H), 4.31 (s, 2H), 4.52 (s, 2H), 6.02 (s, 2H), 6.89 (s, 1H); Mass Spectrum: M+H+ 311 and 313.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[C:8](=[O:20])[N:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1.CI.[CH3:39]N(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:39][O:1][CH2:2][C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)[C:8](=[O:20])[N:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1
Reactant: CN(C)C=O
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CCc3ccccc3)c(=O)c3cc(CO)sc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: COCc1cc2c(=O)n(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a mixture of 4′-{[6-(hydroxymethyl)-2,4-dioxo-3-(2-phenylethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.45 g), methyl iodide (0.11 mL) and N,N-dimethylformamide (5 mL) was added 60% sodium hydride (0.05 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.35 g, 77%).
Reaction SMILES: [C:1]([CH:3]([NH:9][CH:10]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>[NH2:2][C:1]1[S:21][CH:10]=[N:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C#N)NC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1ncsc1N
Yield: 37.9 %

Procedure:
A solution of ethyl 2-cyano-2-formamidoacetate (480 mg, 3.07 mmol) and Lawesson's reagent (746 mg, 1.84 mmol) in toluene (5 mL) was heated up to 80° C. for overnight. The reaction was then diluted with sodium carbonate aqueous solution (20 mL) and methylene chloride (50 mL). Organic phase was washed with brine (20 mL), dried over sodium sulfate and concentrated. Purified with silica gel chromatography to give a solid material of ethyl 5-aminothiazole-4-carboxylate (120 mg). 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 5.98 (s, br, 2H), 4.38 (q, 2H), 1.41 (t, 3H). MS m/z 173.2 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17][CH2:18][C:19]2[C:20]([CH3:35])=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)=[CH:9][CH:8]=1)C.[OH-].[Li+].Cl>C(O)C>[CH3:35][C:20]1[C:19]([CH2:18][O:17][C:10]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=3[C:7]([CH2:6][CH2:5][C:4]([OH:36])=[O:3])=[CH:8][CH:9]=2)=[CH:24][CH:23]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][CH:26]=2)[N:21]=1
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2c1CCCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ccc(CCC(=O)O)c2c1CCCC2
Temperature: 25 °C

Procedure:
160 mg (0.32 mmol) of the above prepared 3-{4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-propionic acid ethyl ester was dissolved in 5 ml of ethanol; 1.0 ml of 2N aqueous lithium hydroxide solution was added and the solution was heated to reflux for 1 hour. Then, the solution was cooled to room temperature and 1.0 ml of 2N aqueous hydrochloric acid was added. The white precipitated solid was filtered off, washed with water, and dried. 140 mg of the title product was thereby obtained as off-white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)=[O:11]
Reactant: CCc1ccc(C(C)=O)cc1
Reactant: COC(OC)N(C)C
Product: CCc1ccc(C(=O)C=CN(C)C)cc1

Procedure:
A mixture of 50 g. of 4'-ethylacetophenone and 50 ml. of dimethylformamide dimethylacetal is refluxed for 16 hours. Evaporation gave a thick oil which crystallized on the addition of hexane, m.p. 80°-81° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]=[C:15]2[C:20]3[CH2:21][NH:22][CH2:23][CH2:24][C:19]=3[NH:18][C:17](=[O:25])[N:16]2[CH:26]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([N:22]1[CH2:23][CH2:24][C:19]2[NH:18][C:17](=[O:25])[N:16]3[CH:26]=[C:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[F:6])[N:14]=[C:15]3[C:20]=2[CH2:21]1)(=[O:4])[CH2:2][CH3:3]
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CNCC2
Reactant: CCC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
Propionyl chloride (39 uL, 0.4 mmol) was added to a solution of 2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (124 mg, 0.4 mmol) and triethylamine (74 uL, 0.5 mmol) in DMF (2 mL) at room temperature. The reaction mixture was stirred for 50 minutes, and then poured into ice water. The precipitate was collected, washed with water and 95% ethanol, and dried to yield 9-propionyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 36) as a white solid, m.p. >310° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Br:14])[N:7]=1.[O:27]1CCOCC1>Br.CC(O)=O>[NH2:1][C:2]1[C:3]([C:25]([NH2:26])=[O:27])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Br:14])[N:7]=1
Reactant: CC(C)n1nc(-c2nc(C#N)c(N)nc2-c2ccccc2Br)ccc1=O
Reactant: C1COCCO1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)n1nc(-c2nc(C(N)=O)c(N)nc2-c2ccccc2Br)ccc1=O
Temperature: 22.5 °C
Reaction time: 5 h

Procedure:
A mixture of 3-amino-5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarbonitrile (59 mg) in 25% hydrogen bromide in AcOH (0.36 ml) was stirred at 20-25° C. for 5 hours. Dioxane (3 ml) was added to the mixture to give a precipitate. The precipitate was collected by filtration and suspended in sat. aq. NaHCO3 to give a solid. The solid was collected by filtration and dried under reduced pressure to give 3-amino-5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarboxamide (17 mg).
Reaction SMILES: [CH3:1][N:2]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)(=[O:5])=[O:4].O.C>C(O)(=O)C.[Fe]>[CH3:1][N:2]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])(=[O:4])=[O:5]
Reactant: CN(OCc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CN(OCc1ccccc1)S(=O)(=O)c1ccccc1N
Reaction time: 0.33 h
Yield: 36.3 %

Procedure:
To a solution of 88.9 g of the product of Example 33 in 565 ml of 90% aqueous acetic acid was added 83 g of iron powder at 80°-90° in several portions. Water (60 ml) was then added and heating continued for 20 minutes. Charcoal (10 g) was added and the solution filtered through Celite® and concentrated in-vacuo. The residue was made strongly alkaline with 20% NaOH solution, then extracted with methylene chloride. The extract was dried and concentrated in-vacuo to give 29.3 g of N-methyl-N-(phenylmethoxy)-2-aminobenzenesulfonamide as a yellow oil. [NMR: δ 5.1 (broad singlet, 2H, NH2)].
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C:24]1[CH:25]=[N:26][C:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)=[N:28][CH:29]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH:39]1([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]O)[CH2:43][CH2:42][CH2:41][CH2:40]1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:16]([C:24]1[CH:29]=[N:28][C:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([O:36][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:35])=[CH:32][CH:31]=2)=[N:26][CH:25]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1
Reactant: OCCCCCCC1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCc1cnc(-c2ccc(C(=O)OCCCCCCC3CCCC3)cc2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 0.3 g of N,N'-dicyclohexyl-carbodiimide in 6 ml of dichloromethane is added dropwise at 0° C. within 15 minutes to a solution of 0.201 g of 4-(5-octyl-pyrimidin-2-yl)-benzoic acid, 0.116 g of cyclopentane-hexanol and 0.02 g of 4-dimethylaminopyridine in 10 ml of dichloromethane. The suspension is stirred at 0° C. for a further 1 hour, filtered and concentrated. The residue is chromatographed on 10 g of silica gel with hexane/ethyl acetate 19:1 (v/v). Recrystallization of the product-containing fractions from ethanol gives pure 6-cyclopentyl-hexyl 4-(5-octyl-pyrimidin-2-yl)-benzoate.
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.C1C=CC=CC=1.[H-].[C:17]([OH:29])(=[O:28])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>C1COCC1>[C:17]([OH:29])(=[O:28])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: C=CCCCCCCCCC(=O)O
Agent: O=C(O)c1ccccc1
Agent: [H-]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCC(=O)O
Reaction time: 2.5 h

Procedure:
Extended reflux of carboxylic acids with excess thexylborane-THF is known to give aldehydes. By contrast TBDA at 0° C. reduces aliphatic carboxylic acids to give predominantly the corresponding alcohols. Benzoic acid in THF is only reduced to the extent of 15% in 48 hours whereas in benzene 1.98 equivalents of hydride are taken up in 2.5 hours. 10-Undecenoic acid reacts only at the double bond with one equivalent of TBDA at 0° C. in 15 minutes. Hydrolysis of the intermediate organoborane gives undecanoic acid in 90% isolated yield.