Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[H][H]>[Ni].CO>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)C=Cc1ccc(Oc2ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COC(=O)CCc1ccc(Oc2ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Yield: 75.1 %

Procedure:
Raney nickel 2800 (21.9 g) was added to a degassed solution of the unsaturated ester 30 (20.0 g) in MeOH (100 mL) and the resulting suspension was treated with hydrogen at atmospheric pressure for 18 h. The suspension was filtered over a Celite® bed and concentrated. Completion of hydrogenation was determined by NMR. Flash chromatography (20-50% ethyl acetate in hexane containing 1% acetic acid) of the resulting residue gave the desired saturated ester 31 (15.1 g, 75%). 1H NMR (400 MHz, DMSO-d6): 12.8 (br, 1H), 7.37 (d, J=8.8 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 4H), 3.59 (s, 3H), 2.84 (t, J=7.6 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H) 1.39 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].[C:20](Cl)(=O)C(Cl)=O>CO>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH3:20])=[O:14]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)O)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Product: COC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Yield: 89 %

Procedure:
2-[(2,6-Dichloro-3-methylphenyl)amino]benzoic acid is reacted with oxalyl chloride and methanol according to the procedure of Example 25 to give 2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid, methyl ester in 89% yield; mp 132°-134° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[CH2:21]([C:24]#[N:25])[C:22]#[N:23].C([O-])([O-])=O.[K+].[K+].Cl>CC#N.O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:21]([C:24]#[N:25])[C:22]#[N:23]
Reactant: N#CCC#N
Reactant: COC(=O)CCCCCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)CCCCCCCCCCCCCCCC(C#N)C#N
Temperature: 80 °C
Reaction time: 18.5 h
Yield: 139.8 %

Procedure:
To 16-bromohexadecanoic acid methyl ester (1.40 g, 4.0 mmol) in MeCN (20 ml) were added malonodinitrile (1.01 g, 15.3 mmol) and K2CO3 (0.92 g, 6.64 mmol). The mixture was stirred at 80° C. for 18.5 h. Water (50 ml) and 1N HCl (50 ml) were added, and the product was extracted with AcOEt. The combined extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure. 1.87 g (100%) of an oil was obtained which crystallized completely after some hours.
Reaction SMILES: CO[C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5]1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C1(C)C(C)=CC=CC=1>[N:11]1([C:3]([CH:4]2[NH:5][C:6](=[O:9])[CH2:7][CH2:8]2)=[O:10])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Reactant: C1COCCN1
Solvent: Cc1ccccc1C
Product: O=C1CCC(C(=O)N2CCOCC2)N1
Temperature: 140 °C

Procedure:
A mixture of 143 g of pyroglutamic acid methyl ester (1 mol) and 139 g morpholine (1.60 mol) in 900 ml of xylene is heated to 140° C. for 20 h. The xylene is evaporated to a volume of 500 ml. From the suspension obtained, the precipitate is filtered off, washed with THF to yield the desired compound after drying in vacuo. From the filtrate the solvent is evaporated completely. This crude product [(R/S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one] is filtered over 800 g silica gel with THF as the solvent and evaporated to dryness to yield a second crop of the desired compound. This compound is used directly in the next step. HPLC analysis shows the material to be in an enantiomeric ratio: 55.8:44.2 [(4-a, R1=H; R4=morpholine): (4-b, R1=H; R4=morpholine), respectively].
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][CH:17]3[CH2:19][CH2:18]3)[CH2:12][CH2:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:20]1[C:24]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=2)=[CH:23][N:22]=[CH:21]1>>[C:1]([C:5]1[N:9]=[C:8]([N:10]2[CH2:11][CH2:12][CH:13]([N:16]([CH:17]3[CH2:19][CH2:18]3)[C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([C:24]4[O:20][CH:21]=[N:22][CH:23]=4)=[N:26][CH:27]=3)[CH2:14][CH2:15]2)[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1noc(N2CCC(NC3CC3)CC2)n1
Reactant: O=C(O)c1ccc(-c2cnco2)nc1
Product: CC(C)(C)c1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)nc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from [1-(3-tert-butyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-cyclopropyl-amine and 6-oxazol-5-yl-nicotinic acid following a procedure analogous to that described in Example 1. LC (method 7): tR=1.16 min; Mass spectrum (ESI+): m/z=437 [M+H]+.
Reaction SMILES: I[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:37])=[C:22]([N:24]2[C:28]([NH2:29])=[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]([CH3:36])=[N:25]2)[CH:23]=1.C1(C(C(C)=O)C#N)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:37])=[C:22]([N:24]2[C:28]([NH:29][C:2]3[CH:10]=[N:9][CH:8]=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])=[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]([CH3:36])=[N:25]2)[CH:23]=1
Reactant: Cc1ccc(F)cc1-n1nc(C)c(-c2ccccc2)c1N
Reactant: O=C(O)c1ccncc1I
Agent: [Cu+2]
Agent: CC(=O)C(C#N)c1ccccc1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1-n1nc(C)c(-c2ccccc2)c1Nc1cnccc1C(=O)O
Temperature: 150 °C
Yield: 10 %

Procedure:
A mixture of 3-iodoisonicotinic acid (180 mg, 0.72 mmol), potassium carbonate (199 mg, 1.44 mmol), 1-(5-fluoro-2-methylphenyl)-3-methyl-4-phenyl-1H-pyrazol-5-amine (202 mg, 0.72 mmol, synthesized in the same manner as Intermediate F, using commercially available 2-phenylacetoacetonitrile as the nitrile source), and copper (II) acetate (6.5 mg, 0.04 mmol) in DMF (1 mL) was heated (150° C.) in a sealed tube for 16 h. The mixture was cooled to rt, filtered through a silica gel plug using ethyl acetate as eluent, concentrated to dryness, and subjected to HPLC purification using a gradient elution from 30% to 90% acetonitrile in water to afford 29.1 mg (10%) of the desired product. 1H NMR (300 MHz, CD3CN) δ 9.39 (br s, 1H), 7.93 (s, 1H), 7.86-7.90 (m, 2H), 7.05-7.45 (m, 8H), 2.38 (s, 3H), 2.15 (s, 3H); ES-MS m/z 403.1 (MH+), HPLC RT (min) 2.40.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:48])=[C:9]([CH2:11][O:12][C:13]2[CH:47]=[CH:46][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([CH:23]=O)[C:20]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[N:36]=[C:37]([C:41]6[O:42][CH:43]=[CH:44][CH:45]=6)[O:38][C:39]=5[CH3:40])=[CH:29][CH:28]=4)=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1.C(OP([CH2:57][C:58]([O:60][CH2:61][CH3:62])=[O:59])(OCC)=O)C.[H-].[Na+]>CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:48])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]3[CH:22]=[C:21](/[CH:23]=[CH:57]/[C:58]([O:60][CH2:61][CH3:62])=[O:59])[C:20]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]5[N:36]=[C:37]([C:41]6[O:42][CH:43]=[CH:44][CH:45]=6)[O:38][C:39]=5[CH3:40])=[CH:31][CH:32]=4)=[N:19]3)=[CH:46][CH:47]=2)[N:10]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccc(OCc4nc(-c5ccco5)oc4C)cc3)cc2C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a mixture of 1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxy]-1H-pyrazol-4-carbaldehyde (14.09 g), ethyl diethylphosphonoacetate (5.88 g), and N,N-dimethylformamide (100 ml), sodium hydride (60%, oily, 1.01 g) was added at 0° C., and the mixture was stirred at room temperature for two hours. The reaction mixture was poured into ice water, and the obtained crystals were collected by filtration, and ethyl(E)-3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxy]-1H-pyrazol-4-yl]propenoate was obtained (13.91 g, yield: 89%). This was recrystallized from ethyl acetate-hexane. Melting point: 138–139° C.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH:21]2[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH3:32])=[C:22]2[C:33]([O:35][CH3:36])=[O:34])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:13][C:12]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH3:32])=[C:22]1[C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc(S(C)(=O)=O)ccc1OCCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc(S(C)(=O)=O)ccc1OCCCCN
Yield: 48.2 %

Procedure:
A solution of 6.9 g of dimethyl 4-[2-(4-phthalimidobutoxy)-5-methylsulfonylphenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and 5.9 g of hydrazine monohydrate in 170 ml of % ethanol(water: 5%) was refluxed under heating for 6 hours. After cooling, the reaction solution was concentrated under reduced pressure. The residue was extracted with chloroform, and the extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Crude crystals thus obtained were recrystallized from chloroform-ether to give 2.6 g of dimethyl 4-[2-(4-aminobutoxy)-5-methylsulfonylphenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5]([CH2:10][OH:11])[N:4]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(F)(F)F.CCOCC>>[OH:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:1][CH2:2][C:3]=2[N:4]=1
Reactant: OCc1ccc(O)c(CO)n1
Reactant: O=Cc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Product: OCc1ccc2c(n1)COC(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a stirred suspension of 31 g. (0.2 mole) of 2,6-bis-(hydroxymethyl)-3-hydroxypyridine (U.S. Pat. No. 3,700,681) in 101 ml. (1 mole) of benzaldehyde at 20°-25° C. is added dropwise over 45 min. 56.7 g. (0.4 mole) of borontrifluoride etherate. The mixture is allowed to stir at room temperature for 2 hrs., and the excess benzaldehyde removed under reduced pressure. The residue, after standing at room temperature, is added to 75 ml. of a 10M aqueous sodium hydroxide solution, and the product extracted into methylene dichloride. The organic phase is separated, concentrated in vacuo to 100 ml. and the methylene dichloride diluted with n-hexane. The crude product which crystallizes is filtered and dried, 37.4 g. (77% yield), m.p. 85°-89° C. Further purification is effected by recrystallization from acetone-n-hexane, 22.1 g., m.p. 114°-118° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])C=O.ClC1C=CC=C([C:30]([O:32]O)=[O:31])C=1>C(Cl)Cl>[CH:30]([O:32][C:10]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:9]=1)=[O:31]
Reactant: COCCOCOc1ccc(C=O)cc1OCOCCOC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCCOCOc1ccc(OC=O)cc1OCOCCOC
Yield: 86 %

Procedure:
5.4 g (17 mmol) of 3,4-di(2-methoxyethoxymethoxy)benzaldehyde was dissolved in 216 ml of methylene chloride, and 80% m-chloroperbenzoic acid was added thereto. The mixture was refluxed at a boiling point for 20 hours. The reaction solution was washed with a sodium bicarbonate aqueous solution and with a saturated sodium chloride aqueous solution and then dried. The solvent was distilled off under reduced pressure to obtain 4.85 g (yield: 86%) of O-formyl-3,4-di(2-methoxyethoxymethoxy)phenol. The product was used for the subsequent reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C:13]23[CH2:20][CH2:19][C:16](C4C=CC=C(OC5C=CC=CC=5)C=4)([CH2:17][CH2:18]2)[O:15][CH2:14]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.BrC1C=CC=C(OC2C=CC=CC=2)C=1.[CH3:48][C:49]1[S:50][CH:51]=[C:52]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:53]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C:13]23[CH2:20][CH2:19][C:16]([C:51]4[S:50][C:49]([CH3:48])=[N:53][C:52]=4[C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)([CH2:17][CH2:18]2)[O:15][CH2:14]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(c4cccc(Oc5ccccc5)c4)(CC2)OC3)cc1
Reactant: Cc1nc(-c2ccccc2)cs1
Agent: Brc1cccc(Oc2ccccc2)c1
Product: Cc1ccc(S(=O)(=O)OCC23CCC(c4sc(C)nc4-c4ccccc4)(CC2)OC3)cc1

Procedure:
(1-(2-Methyl-4-phenylthiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate was prepared using a procedure analogous to (1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate except that 1-bromo-3-phenoxybenzene was replaced with 2-methyl-4-phenylthiazole. The title compound was obtained (0.125 g, 0.266 mmol, 62.1% yield) as a light yellowish oil. LCMS, [M+H]+=470.1. 1H NMR (500 MHz, CDCl3) δ 7.77-7.72 (m, 2H), 7.43-7.32 (m, 7H), 3.75 (s, 2H), 3.66 (s, 2H), 2.64 (s, 3H), 2.45 (s, 3H), 2.08-1.99 (m, 2H), 1.82 (ddd, J=13.3, 11.6, 4.3 Hz, 2H), 1.61 (qd, J=7.2, 3.0 Hz, 2H), 1.43 (td, J=12.4, 4.8 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:10][CH2:11][C@@H:12]2[C@:21]3([CH3:22])[C@H:16]([C:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][CH2:20]3)[CH2:15][CH2:14][C@@:13]2([CH3:26])O)[CH:6]=[C:7]([CH3:9])[CH:8]=1.Cl[Sn](Cl)(Cl)Cl.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]2[C:4]=1[C@@:13]1([CH3:26])[C@H:12]([CH2:11][S:10]2)[C@:21]2([CH3:22])[C@H:16]([C:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]1
Reactant: COc1cc(C)cc(SC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2
Temperature: 0 °C
Yield: 55 %

Procedure:
To a solution of (1R,2R,4aS,8aS)-1-{[(3-methoxy-5-methylphenyl)-sulfanyl]methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (13) (5.70 g, 15.1 mmol) in CH2Cl2 (300 mL) was added dropwise SnCl4 (1 M in CH2Cl2, 60 mL, 60 mmol) at −78° C. over 20 min. After complete addition, the reaction mixture was allowed to warm to 0° C. for 1 h. Water (50 mL) was added at 0° C. The organic layer was separated, dried (Na2SO4), and concentrated. Trituration with EtOAc (60 mL) gave (1R,10R,11S,16S)-3-methoxy-1,5,11,15,15-pentamethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 14) (1.44 g, batch 1) as a white solid. The filtrate was recrystallized to afford an additional batch (1.56 g, total yield 55%) as white crystals. 1H NMR (CDCl3): δ 6.52 (d, 1H), 6.38 (d, 1H), 3.78 (s, 3H), 3.30 (m, 1H), 2.84 (m, 1H), 2.76 (m, 1H), 2.20 (s, 3H), 1.84-1.40 (m, 8H), 1.38 (s, 3H), 1.34-1.00 (m, 3H), 0.95 (s, 3H), 0.86 (s, 3H), 0.86 (s, 3H). MS m/z 359 (C23H34OS+H+).
Reaction SMILES: I[C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:3]=1.[CH:15]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([CH3:17])[CH3:16].C([O-])(O)=O.[Na+].O>O1CCOCC1.CCOC(C)=O.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>[CH:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:6]([CH:7]=[O:8])=[CH:5][N:4]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[N:3]=2)=[CH:21][CH:20]=1)([CH3:17])[CH3:16]
Reactant: O=Cc1cn(C2CCCCO2)nc1I
Reactant: CC(C)Oc1ccc(B(O)O)cc1
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: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nn(C3CCCCO3)cc2C=O)cc1
Yield: 90.2 %

Procedure:
To a solution of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde (8 g, 26.1 mmol) in 1,4-dioxane (240 mL) were added 4-isopropoxy phenylboronic acid (5.3 g, 27.36 mmol) and sat. NaHCO3 solution (50 mL). The reaction mixture was degassed under argon for 0.5 h. Tetrakis(triphenylphosphine)palladium (1.2 g, 1.03 mmol) was added under an argon atm. and the resultant suspension was heated for 8 h at 90° C. The reaction was poured into water (500 mL) and extracted with EtOAc (100 mL×3). The combined extracts was washed with brine (300 mL) dried and concentrated under vacuum. The residue was purified by SGC using Hex:EtOAc (0%-40%) as eluent to obtain 3-(4-isopropoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde (7.4 g, Yield 90%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8](OCC)=O)=[N:4][NH:5][C:6]=1C.C[C:14]1NN=[C:16]([N:19](CCC)[CH2:20][CH2:21][CH3:22])[CH:15]=1>>[Cl:1][C:2]1[C:6]([N:19]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15][CH3:14])=[N:5][NH:4][C:3]=1[CH3:8]
Reactant: CCCN(CCC)c1cc(C)[nH]n1
Reactant: CCOC(=O)c1n[nH]c(C)c1Cl
Product: CCCN(CCC)c1n[nH]c(C)c1Cl
Yield: 61 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1A, 5-methyl-N,N-dipropyl-1H-pyrazol-3-amine (400 mg, 2.21 mmol) was converted to the title compound (290 mg, 61%). 1H NMR (CDCl3) δ 3.20-3.16 (m, 4H), 2.18 (s, 3H), 1.55 (sxt, J=7.5 Hz, 4H), 0.88 (t, J=7.4 Hz, 6H); MS(ESI+) m/z 216.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.[N-:20]=[N+:21]=[N-:22].[Na+].[NH4+].[Cl-]>CN(C=O)C>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]2[NH:22][N:21]=[N:20][N:14]=2)=[CH:10][CH:11]=1
Reactant: N#CCc1ccc(OCc2c(F)cccc2F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1COc1ccc(Cc2nnn[nH]2)cc1
Temperature: 90 °C

Procedure:
A mixture of (4-(2,6-Difluorobenzyloxy)phenyl)-acetonitrile (Step A, 5 g, 19.3 mmol), NaN3 (1.3 g, 20 mmol), and NH4Cl (1.06 g, 20 mmol) in dry DMF (60 ml) was heated at 90° C. for 16 hours. The solvent was removed in vacuo and the oily residue was partitioned between EtOAc and water (acidified to pH 1 with conc. HCl). The organic layer was washed with water, dried over Na2SO4, filtered and concentrated to a brown semisolid. The purification was done by flash chromatography on silica gel column (chloroform:methanol, 9:1) to provide the title compound as a light creamy solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH2:13][CH:12]([OH:14])[CH2:11][C:10]([CH3:16])([CH3:15])[C:9]=1/[CH:17]=[CH:18]/[CH:19]([OH:21])[CH3:20]>[O-2].[O-2].[Mn+4]>[CH3:7][C:8]1[CH2:13][CH:12]([OH:14])[CH2:11][C:10]([CH3:15])([CH3:16])[C:9]=1/[CH:17]=[CH:18]/[C:19]([CH3:20])=[O:21]
Reactant: CC1=C(/C=C/C(C)O)C(C)(C)CC(O)C1
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Product: CC(=O)/C=C/C1=C(C)CC(O)CC1(C)C

Procedure:
The ketone 1 prepared from isophorone is reacted with a Grignard reagent prepared from but-3-yn-2-ol to give the diol 2, from which the dihydroxyketone 3 is formed by eliminating the ethylenedioxy protective group. The dihydroxyketone 3 can be reduced with lithium aluminum hydride to the triol 4, which can be reacted with acetic anhydride in pyridine to give the acetate 5. Dehydration of 5 with phosphoryl chloride in pyridine gives the enyne diacetate 7, which can be reduced with lithium aluminum hydride to the enynediol 6 and, when the reaction is carried out under more stringent conditions, to 3-hydroxy-β-ionol. Selective oxidation of 8 with manganese dioxide gives 3-hydroxy-β-ionone 9. Reaction of the latter with vinyl magnesium bromide gives the vinyl alcohol 10, which, when treated with triphenylphosphonium bromide, forms the Wittig reagent 11. When the latter is heated with the dialdehyde 12 in 1,2-epoxybutane, zeaxanthin 14 is obtained in good yield. Condensation of the Wittig salt 11 with (C25 -)-β-apo-12'-carotenal 16 in 1,2-epoxybutane gives β-cryptoxanthin 18, or condensation of 11 with racemic (C25 -)-α-apo-12'-carotenal gives zeinoxanthin 17. Equation 1 below illustrates the synthetic route described:
Reaction SMILES: NC1C2CCCCC=2C=CC=1.N(C1C2CCCCC=2C=CC=1)C(C)=O.C(NC1C=CC=CC=1)(=O)C.[NH:36]([C:40]1[C:49]2[CH2:48][CH2:47][CH2:46][CH2:45][C:44]=2[C:43]([N+:50]([O-:52])=[O:51])=[CH:42][CH:41]=1)C(C)=O>>[NH2:36][C:40]1[C:49]2[CH2:48][CH2:47][CH2:46][CH2:45][C:44]=2[C:43]([N+:50]([O-:52])=[O:51])=[CH:42][CH:41]=1
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c2c1CCCC2
Agent: CC(=O)Nc1cccc2c1CCCC2
Agent: CC(=O)Nc1ccccc1
Agent: Nc1cccc2c1CCCC2
Product: Nc1ccc([N+](=O)[O-])c2c1CCCC2

Procedure:
1-Amino-5,6,7,8-tetrahydronaphthaline was converted to 1-acetamino-5,6,7,8-tetrahydronaphthaline according to Method A2a, Step 1. The acetanilide was converted to 1-acetamino-4-nitro-5,6,7,8-tetrahydronaphthaline according according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 1-amino-4-nitro-5,6,7,8-tetrahydronaphthaline. The aniline was converted to 4-nitro-5,6,7,8-tetrahydro-1-naphthyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-nitro-5,6,7,8-tetrahydro-1-naphthyl isothiocyanate according to Method C1a to give 2-(4-nitro-5,6,7,8-tetrahydro-1-naphthylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(4-nitro-5,6,7,8-tetrahydro-1-naphthylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: CC(C)[C@H](N1CC2C(=CC(C3C=CC(NC(C4SC(C5C=CC=CC=5)=CN=4)=O)=CC=3)=CC=2)C1=O)C(OC)=O.[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:54]=[C:53]3[C:49]([CH2:50][N:51]([C@@H:56]([CH:61]([CH3:63])[CH3:62])[C:57]([O:59][CH3:60])=[O:58])[C:52]3=[O:55])=[CH:48][CH:47]=2)=[CH:42][CH:41]=1.[C:64]1([C:70]2[NH:71][C:72]([C:75](OCC)=[O:76])=[N:73][N:74]=2)[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>>[CH3:62][CH:61]([CH3:63])[C@H:56]([N:51]1[CH2:50][C:49]2[C:53](=[CH:54][C:46]([C:43]3[CH:42]=[CH:41][C:40]([NH:39][C:75]([C:72]4[NH:71][C:70]([C:64]5[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=5)=[N:74][N:73]=4)=[O:76])=[CH:45][CH:44]=3)=[CH:47][CH:48]=2)[C:52]1=[O:55])[C:57]([O:59][CH3:60])=[O:58]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: CCOC(=O)c1nnc(-c2ccccc2)[nH]1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4nnc(-c5ccccc5)[nH]4)cc3)cc2C1=O

Procedure:
The compound of example 628 was prepared analogous to the compound of example 611 by reaction of compound of example 6 with ethyl 5-phenyl-4H-1,2,4-triazole-3-carboxylate.