Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14](Cl)=[N:15][OH:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:25]([C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:26]=[C:25]([C:27]4[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=4)[O:16][N:15]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: ON=C(Cl)Cc1ccc(Oc2ccc(F)cc2)nc1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ncccc1-c1cc(Cc2ccc(Oc3ccc(F)cc3)nc2)no1
Temperature: 55 °C
Reaction time: 5 h
Yield: 31.9 %

Procedure:
To a mixture of (6-(4-fluoro-phenoxy)-pyridin-3-yl)-acetohydroximoyl chloride (25 mg) described in Manufacturing Example 75-1-4 and tetrahydrofuran (1 mL) were added 3-ethynyl-pyridin-2-ylamine (6.0 mg, 0.051 mmol) described in Manufacturing Example 1-2-3 and triethylamine (21 μL, 0.15 mmol), which was stirred for 5 hours at 55° C. The reaction mixture was cooled to room temperature and water was added thereto at that temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (5.9 mg, 32%).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH:14]1[C:20]([OH:22])=[O:21])=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH3:23]COC(C)=O.[NH4+].[Cl-]>C1COCC1.O>[CH3:23][O:21][C:20]([CH:14]1[CH2:15][C:16]([CH2:3][CH:2]=[CH2:1])([OH:19])[CH2:17][CH2:18][N:13]1[C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1C(=O)O
Reactant: CCOC(C)=O
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC1(O)CCN(C(=O)OC(C)(C)C)C(C(=O)OC)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a stirred solution n-butyllithium (165 mg, 2.6 mmol) in THF (5 mL) at −78° C. was added 12a (P=Boc, P2=Me, m=1) (570 mg, 2.3 mmol) in THF (5 mL). The reaction mixture was stirred at −78° C. for 2 h and then at −40° C. for an additional 1 h. EtOAc (20 mL) was added, followed by NH4Cl (5 mL, 10%) and water (10 mL). Organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue obtained was purified by silica gel column chromatography using 50% EtOAc in hexanes as eluant to provide 4-hydroxy-4-butylproline methyl ester 12b (P=Boc, m=1, R9=n-butyl) as a colorless oil (0.52 g, 73%): 1H NMR (300 MHz, CDCl3) δ 4.33 (m, 1), 3.76 (d, J=4.8, 3), 3.62 (m, 2), 3.28 (m, 1), 2.13 (m, 1), 2.02 (m, 1), 1.57 (m, 2), 1.29 (m, 12), 0.88 (m, 3); MS (ESPOS): 324 [M+Na]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.C(=O)(O)[O-].[Na+].[C:14]([O:17][C:18]1[CH:42]=[CH:41][C:40](Br)=[CH:39][C:19]=1[C:20]([NH:22][C:23]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])=[O:21])(=[O:16])[CH3:15]>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.C(OCC)(=O)C.O.COCCOC>[C:14]([O:17][C:18]1[CH:42]=[CH:41][C:40]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:39][C:19]=1[C:20]([NH:22][C:23]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])=[O:21])(=[O:16])[CH3:15]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Br)ccc1OC(C)=O
Reactant: OB(O)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccco2)ccc1OC(C)=O
Temperature: 25 °C
Yield: 53.6 %

Procedure:
Water (0.42 mL), 2-furanboronic acid (0.040 g), sodium bicarbonate (0.060 g), and bis(triphenylphosphine)palladium(II) dichloride (4 mg) were added to an ethylene glycol dimethyl ether (1.4 mL) suspension of methyl 2-(2-acetoxy-5-bromobenzamido)-4-phenylbenzoate (0.14 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 10 minutes. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-70% hexane/ethyl acetate] and further purified by silica gel column chromatography [eluent: 90-70% hexane/ethyl acetate] to obtain 0.073 g of methyl 2-(2-acetoxy-5-(furan-2-yl)benzamido)-4-phenylbenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[CH:18]=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:18]=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCOc1ccc2cc(-c3ccc4ccc(Cl)cc4n3)oc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCOc1ccc2cc(-c3ccc4ccc(Cl)cc4n3)oc2c1
Yield: 55.4 %

Procedure:
A mixture of 7-chloro-2-[6-[3-(ethoxycarbonyl)-propoxy]benzofuran-2-yl]quinoline (1.26 g) and potassium hydroxide (1.51 g) in a mixture of ethanol (12 ml) and water (6 ml) was stirred under reflux for one hour. After being cooled, the resulting precipitates were collected by filtration, washed with ethanol and added to water. The mixture was adjusted to pH 7 with diluted aqueous hydrochloric acid. The resulting crystals were collected by filtration, washed with water, and recrystallized from a mixture of acetic acid and methanol to give 7-chloro-2-[6-(3-carboxypropoxy)benzofuran-2-yl]quinoline (0.65 g).
Reaction SMILES: C1(C2OC(C(F)(F)F)=C(C(NC3C=CC(C4C=CC(C([C@@H]5CCC[C@H]5C(O)=O)=O)=CC=4)=CC=3)=O)N=2)C=CC=CC=1.[C:41]1([C:47]2[O:48][C:49]([C:78]([F:81])([F:80])[F:79])=[C:50]([C:52]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]4[CH:66]=[CH:65][C:64]([C:67]([CH:69]5[CH2:74][CH2:73][CH2:72][CH2:71][CH:70]5[C:75]([OH:77])=[O:76])=[O:68])=[CH:63][CH:62]=4)=[CH:57][CH:56]=3)=[O:53])[N:51]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C1(C2OC(C(F)(F)F)=C(C(O)=O)N=2)C=CC=CC=1.NC1C=CC(C2C=CC(C([C@@H]3CCCC[C@H]3C(O)=O)=O)=CC=2)=CC=1>>[C:41]1([C:47]2[O:48][C:49]([C:78]([F:80])([F:81])[F:79])=[C:50]([C:52]([NH:54][C:55]3[CH:56]=[CH:57][C:58]([C:61]4[CH:66]=[CH:65][C:64]([C:67]([C@H:69]5[CH2:74][CH2:73][CH2:72][CH2:71][C@@H:70]5[C:75]([OH:77])=[O:76])=[O:68])=[CH:63][CH:62]=4)=[CH:59][CH:60]=3)=[O:53])[N:51]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Nc1ccc(-c2ccc(C(=O)C3CCCCC3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Nc1ccc(-c2ccc(C(=O)[C@@H]3CCCC[C@H]3C(=O)O)cc2)cc1
Agent: O=C(Nc1ccc(-c2ccc(C(=O)[C@@H]3CCC[C@H]3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1ccc(-c2ccc(C(=O)[C@H]3CCCC[C@@H]3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a method similar to that used for the preparation of racemic trans-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclopentanecarboxylic acid above, racemic 2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic trans-2-(4′-amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid. The racemic product obtained was separated by chiral SFC to afford (1S,2S)-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclohexanecarboxylic acid (or enantiomer). [α]D:−23° in DMSO. LCMS calcd for C31H25F3N2O5 (m/e) 562, obsd 563 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=C(C)C(O)=[CH:14][CH:15]=2)[C:10]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])([OH:19])[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].ClCCl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:16][C:11]([CH:10]=[O:19])=[CH:14][CH:15]=2)[C:10]([CH2:20][C:21]([N:23]([CH3:24])[CH3:25])=[O:22])([OH:19])[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(O)ccc2c1C(O)(CC(=O)N(C)C)C(=O)N2Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CN(C)C(=O)CC1(O)C(=O)N(Cc2ccccc2)c2ccc(C=O)cc21
Yield: 198.6 %

Procedure:
Under inert atmosphere, a flask is charged with manganese dioxide (8.7 g, 0.1 mop and 2-(1-benzyl-3-hydroxy-5-hydroxy-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide (Example 23) (3.54 g, 0.01 mol). To this, mol sieve (4 A, 2 g) and dichloromethane (100 mL) are added, and the mixture is heated under reflux for six hours. The mixture is then filtered, and evaporation of the solvent leaves 3.5 g of a dark brown foam. This is chromatographed on silica (ethyl acetate) to give 1.8 g (50%) of the title product as pale yellow foam. 1H-NMR (CDCl3, 300 MHz) δ 2.82, 3.13 (AB, 2H, 2J=16.1Hz, CH2NMe2); 2.95, 2.98 (2 s, 3H each, N(CH3)2); 4.93, 4.94 (AB, 2H, 2J=16 Hz, NCH2Ph); 6.11 (s, 1H, OH); 6.82 (d, 1H, 3J=7.9 Hz, H-7); 7.23-7.38 (m, 5H, Ph); 7.72 (dd, 1H, 4J=1.5 Hz, H-6); 8.00 (d, 1H, H-4); 9.83 (s, 1H, CHO). 13C-NMR (CDCl3, 75 MHz) δ 35.76, 37.70 (N(CH3)2); 38.72 (CH2CONMe2); 44.42 (NCH2Ph); 74.06 (C-3); 109.80 (C-7); 125.38 (C-4); 127.42 (Bn ortho-C); 128.14 (Bn para-C); 129.16 (Bn meta-C); 132.00, 132.31 (C-5, C-9); 133.49 (C-6); 135.04 (Ph ipso-C); 148.24 (C-8); 170.22 (CONMe2); 176.69 (C-2); 190.80 (CHO).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][CH2:7][C:8]([OH:10])=O.[CH3:11][NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16](=[O:30])[C:17]1[C:22]([I:23])=[C:21]([NH2:24])[C:20]([I:25])=[C:19]([C:26]([OH:28])=[O:27])[C:18]=1[I:29]>CC(N(C)C)=O>[CH3:11][NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16](=[O:30])[C:17]1[C:22]([I:23])=[C:21]([NH:24][C:8](=[O:10])[CH2:7][O:6][CH3:5])[C:20]([I:25])=[C:19]([C:26]([OH:28])=[O:27])[C:18]=1[I:29]
Reactant: CNC(=O)CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: COCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CNC(=O)CNC(=O)c1c(I)c(NC(=O)COC)c(I)c(C(=O)O)c1I
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At maximally 10° C., 29.0 ml. of thionyl chloride is added dropwise under agitation to 28.2 ml. of methoxyacetic acid in 100 ml. of dimethylacetamide within 40 minutes. After, at 0° C., the reaction mixture has been agitated for another 2 hours, 63.0 g. (0.1 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine methylamide (IVa), m.p. 252°-253° C. (decomposition), in 100 ml. of dimethylacetamide is added dropwise under agitation to the reaction mixture at maximally 8° C. during the course of one hour. Then, the solution is agitated overnight. After the addition of 5 ml. of water, the mixture is concentrated under vacuum, the residue is stirred with 700 ml. of water, the precipitate is vacuum-filtered, carefully washed with water, and, while still moist, reprecipitated from dilute ammonia with concentrated hydrochloric acid. After allowing the mixture to stand for some time, the acid is vacuum-filtered, washed well with water, stirred with fresh water, and, after another filtering step, dried under vacuum at 70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([O:15][Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH2:13][NH2:14])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:23][C:24]([CH3:28])([CH3:27])[CH:25]=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([O:15][Si:16]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:21][CH3:22])[CH2:13][NH:14][CH2:23][C:24]([CH3:28])([CH3:27])[CH3:25])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC(C)(C)C=O
Reactant: CC[Si](CC)(CC)OC(CN)c1c(Cl)cnc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(CNCC(C)(C)C)c1c(Cl)cnc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a yellow clear solution of 2-(3-chloroquinolin-4-yl)-2-((triethylsilyl)oxy)ethanamine (A275-6) (0.217 g, 0.644 mmol) in DCM (2.15 mL) was added trimethylacetaldehyde (0.077 mL, 0.71 mmol), AcOH (0.045 mL, 0.77 mmol), and NaBH(OAc)3 (0.205 g, 0.966 mmol). The yellow homogeneous mixture was stirred at room temperature. After 2 h, the mixture was quenched with water (20 mL) and neutralized with 0.5 M NaOH (10 mL) to pH ˜9.0. The reaction mixture was extracted with DCM (2×50 mL). The organic extract washed with saturated NaCl (1×50 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow syrup. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (40 g), eluting with a gradient of 0% to 20% EtOAc in hexane, and dried under high vacuum to give N-(2-(3-chloroquinolin-4-yl)-2-((triethylsilyl)oxy)ethyl)-2,2-dimethylpropan-1-amine (A275) as colorless syrup. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (1H, s), 8.75 (1H, d, J=7.2 Hz), 8.04 (1H, dd, J=8.4, 1.0 Hz), 7.77 (1H, ddd, J=8.4, 6.9, 1.4 Hz), 7.61-7.68 (1H, m), 5.70 (1H, dd, J=7.7, 5.0 Hz), 3.26 (1H, dd, J=12.6, 8.1 Hz), 2.85 (1H, dd, J=12.6, 5.0 Hz), 2.23-2.39 (2H, m), 1.72 (1H, br. s.), 0.81 (9H, s), 0.72-0.79 (9H, m), 0.36-0.56 (6H, m); LCMS (ESI) m/z 407.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:11]#N)=[C:7]([C:9]#[N:10])[N:8]=1)[CH2:2][CH3:3].[C:13]([Mg]Cl)([CH3:16])([CH3:15])[CH3:14].C([O:21]CC)C>>[CH2:1]([C:4]1[NH:8][C:7]([C:9]#[N:10])=[C:6]([C:11](=[O:21])[C:13]([CH3:16])([CH3:15])[CH3:14])[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(C#N)c(C#N)[nH]1
Reactant: CC(C)(C)[Mg]Cl
Reactant: CCOCC
Product: CCCc1nc(C(=O)C(C)(C)C)c(C#N)[nH]1

Procedure:
Following a procedure similar to that described in Preparation 40, but using 3.2 g of 2-propylimidazole-4,5-dicarbonitrile (prepared as described in Preparation 10) and 33 ml of a 2M solution of t-butylmagnesium chloride in diethyl ether, 2.35 g of the title compound were obtained as crystals, melting at 176°-178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][NH2:12]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][NH:12][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C=O)cc1
Solvent: CC(C)O
Product: COc1ccc(CNNCc2ccc(OC)cc2)cc1

Procedure:
Di-(4-methoxybenzyl) azine was first prepared by reacting 2 moles of p-methoxybenzaldehyde with 1 mole hydrazine in isopropyl alcohol at 10° C. Di-(4-methoxybenzyl) hydrazine was obtained by reacting the azine with diborane in tetrahydrofurane under nitrogen atmosphere at or below 10° C. and isolated as an oil. The dihydrochloride salt of bis-(4-methoxybenzyl) hydrazine was obtained as white solid by mixing with hydrogen chloride gas in isopropanol followed by addition of methylene chloride and toluene (81% yield based on azine). 1,2-Di-(4-methoxybenzyl)hydrazine (3.5 g., 0.01 mole) and 1,3-dimorpholine-1,2-nitropropane (2.6 g., 0.01 mole) were suspended in a mixture of 30 ml of methanol and 20 ml of toluene and heated to reflux for 3 hr. The reaction mixture was evaporated to dryness and the residue extracted with toluene and filtered. The toluene filtrate was evaporated to give 3.5 g. brown oil which was purified by column chromatography using 10% diethyl ether--90% methylene chloride on silica gel. Nuclear Magnetic Resonance and mass spectra confirmed the structure of title compound. The oil solidified after one day standing at room temperature.
Reaction SMILES: [F:1]/[C:2](=[C:13](/[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][CH3:28])[O:21][C:20]([CH3:30])([CH3:29])[CH:19]=[C:18]2[CH:31]([CH3:33])[CH3:32])\[CH3:14])/[CH:3]=[CH:4]/[C:5](/[CH3:12])=[CH:6]/[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C(O)C.C1COCC1>[F:1]/[C:2](=[C:13](/[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][CH3:28])[O:21][C:20]([CH3:30])([CH3:29])[CH:19]=[C:18]2[CH:31]([CH3:32])[CH3:33])\[CH3:14])/[CH:3]=[CH:4]/[C:5](/[CH3:12])=[CH:6]/[C:7]([OH:9])=[O:8]
Reactant: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)OCC)C(C(C)C)=CC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)O)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure G, a solution of ethyl (2E,4E,6E)-6-fluoro-7-(4-isopropyl-2,2-dimethyl-7-propoxy-2H-chromen-6-yl)-3-methyl-octa-2,4,6-trienoate (Compound 112, 73 mg, 0.16 mmo) in ethanol and THF was hydrolyzed with NaOH to yield the title compound as a yellow solid after recrystallized from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 94 %

Procedure:
To a Solution of 4-chloro-3-nitrobenzoic acid (5.0 g, 24.81 mmol) in 50 ml of methanol was added H2SO4 (2 ml, 37.02 mmol) and the reaction mixture was heated at 70° C. for 5 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. Water (50 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was, dried (Na2SO4), filtered and concentrated to give the desired product (5.04 g, 94%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=O.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>C(O)C>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([C:3]2[N:19]=[C:20]3[N:24]([CH:2]=2)[CH:23]=[CH:22][S:21]3)[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Nc1nccs1
Reactant: COc1cc(C(=O)CBr)ccc1-c1ccccn1
Solvent: CCO
Product: COc1cc(-c2cn3ccsc3n2)ccc1-c1ccccn1

Procedure:
A solution of 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone (520 mg, 1.7 mmol) and 2-aminothiazole (170 mg, 1.7 mmol) in ethanol (10 mL) was heated to reflux for 12 h, then concentrated. The residue was dissolved in ethyl acetate (25 mL) and washed with a solution of saturated aqueous sodium bicarbonate (25 mL), then dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc to MeOH:EtOAc (1:19) to afford 6-(3-methoxy-4-pyridin-2-ylphenyl)imidazo[2,1-b][1,3]thiazole.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([O-])=[O:4].[O-]CC.[Mg+2].[O-]CC.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O>CO.O1CCCC1>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:3]([CH2:2][C:1]([O:7][CH3:8])=[O:6])=[O:4]
Reactant: COC(=O)CC(=O)[O-]
Reactant: O=C(O)c1cccs1
Agent: CC[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
In 200 mL of methanol, was dissolved 8.90 g (75.4 mmol) of monomethyl malonate, and the resulting solution was mixed with 4.30 g (37.5 mmol) of magnesium ethoxide, followed by stirring for 4 hours at room temperature. The reaction solution was concentrated and the residue was dried under reduced pressure. In 150 mL of tetrahydrofuran, was dissolved 4.80 g (37.5 mmol) of 2-thiophenecarboxylic acid and the resulting solution was mixed with 6.69 g (41.2 mmol) of carbonyldiimidazole, followed by stirring for 1 hour. The reaction solution was added to a dry magnesium salt and stirred at room temperature for 21 hours. The reaction solution was concentrated; the residue was mixed with 150 mL of 1.5 N hydrochloric acid, extracted with ethyl acetate, and washed with an aqueous sodium hydrogencarbonate solution and then saturated sodium chloride water. The resultant was dried over sodium sulfate anhydride, filtered, and concentrated. The residue was distilled (0.06 mmHg, 87) to give 5.95 g (32.3 mmol, 86.1%) of methyl 2-thiophenecarbonylacetate as an anhydrous liquid. Similarly to Example 133, 2.52 g (8.28 mmol, 81.2%) of yellow crystals were obtained from 5.95 g (32.2 mmol) of methyl 2-thiophenecarbonylacetate by recrystallization from methanol.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[CH2:2][CH3:3].[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[CH:7]=1)[CH2:2][CH3:3]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCCNC(=O)c1cccc(Br)c1
Product: CCCNC(=O)c1cccc(-c2ccc(F)cc2)c1
Yield: 70 %

Procedure:
Using Preparation Method 2, N-n-propyl-3-bromobenzamide from Example 1A as reacted with 4-fluorophenylboronic acid. The resulting reaction mixture was purified using SiO2 with CH2Cl2/Petroleum Ether 80:20 to CH2Cl2/Ethyl Acetate 80:20 to give a white solid (70%). NMR 1H (ppm, CDCl3): 7.94 (t, J4=2.1 Hz, 1H), 7.66 (tt, J3=7.8 Hz, J4=0.9 Hz, 2H), 7.58-7.53 (m, 2H), 7.47 (t, J3=7.8 Hz, 1H), 7.13 (t, J3=9 Hz, 2H), 6.12 (br. s., 1H), 3.47-3.40 (m, 2H), 1.65 (sext., J3=7.5 Hz, 2H), 0.99 (t, J3=7.44 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[OH:12].[CH2:13]([O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([C:34](Cl)=[O:35])[CH:28]=[CH:27]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O1CCOCC1.N1C=CC=CC=1>O>[CH2:13]([O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([C:34]([NH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[OH:12])=[O:35])[CH:28]=[CH:27]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCOc1ccc2cc(C(=O)Cl)ccc2c1
Reactant: CCCCc1ccc(O)c(N)c1
Solvent: C1COCCO1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCOc1ccc2cc(C(=O)Nc3cc(CCCC)ccc3O)ccc2c1
Temperature: 75 °C
Yield: 86.8 %

Procedure:
In a 50 ml three-neck flask, 0.40 g (2.42 m mole) of 2-amino-4-butylphenol, 0.85 g (2.74 m mole) of 6-decyloxy-2-naphthoic acid chloride and 10 ml of dioxane were placed. To the mixture, 0.81 ml of pyridine was added dropwise under stirring at ca. 75° C. of mixture temperature. After the reaction, the reaction mixture was poured into 80 ml of water to precipitate a crystal. The crystal was filtered, washed with water and recrystallized from acetone to obtain 1.00 g of 2-(6-decyloxy-2-naphthoylamino)-4-butylphenol (Yield: 86.5%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH:10](OCC)[O:11]CC.O>C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH:10]=[O:11]
Reactant: CCOC(C#CCCCCCCCl)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=CC#CCCCCCCCl
Temperature: 62.5 °C
Yield: 97 %

Procedure:
In a reactor equipped with a stirrer, a cooling condenser, a dropping funnel and a thermometer were placed 9-chloro-1,1-diethoxy-2-nonyne (246.8 g:1.0 mol), para-toluenesulfonic acid (8.0 g:0.05 mol), water (170.0 g) and tetrahydrofuran (42.0 g), and stirred at a reaction mixture temperature of from 60 to 65° C. During stirring, the pressure in the reactor was reduced gradually to 26.7 KPa to distill off refluxing ethanol. After stirring for 5 hours, completion of the reaction was confirmed by gas chromatography. The organic phase separated from the aqueous phase of the reaction mixture was washed with a solution of sodium chloride (5.0 g) in water (150.0 g). The organic phase was subjected to removal of the solvent under reduced pressure, and then the residue was distilled under reduced pressure to obtain 9-chloro-2-nonynal [bp: 82-88° C./0.13 KPa, 167.2 g, 0.97 mol]. [Yield: 96.9%]