Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([C:17]3[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cn1cncc1Br
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cncn2C)CCN(C)C1
Yield: 2.7 %

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.4 g, 2 mmol), 5-bromo-1-methyl-1H-imidazole (0.644 g, 4 mmol), K3PO4 (0.848 g, 4 mmol), CuI (38 mg, 0.2 mmol) and L-Proline (46 mg, 0.39 mmol) in dry DMF (6 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-methyl-3H-imidazol-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (15 mg). 1H NMR (HCl salt, CD3OD) d (ppm): 9.20 (s, 1H), 8.0 (s, 1H), 7.40 (s, 1H), 7.20 (d, 1H), 7.10 (d, 1H), 4.76 (d, 1H), 4.40 (d, 1H), 3.84 (m, 1H), 3.62 (m, 1H), 3.58 (d, 3H), 3.18 (s, 3H), 3.05 (m, 1H), 2.90 (m, 1H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]([CH2:24][CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:9]1[C:10]([N+:21]([O-:23])=[O:22])=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([CH:17]=1)[C:14](O)=[O:15])(=[O:4])=[O:3].[NH2:31][CH2:32][CH:33]([OH:36])[CH2:34][OH:35].Cl>>[CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]([CH2:24][CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:9]1[CH:17]=[C:13]([C:14]([NH:31][CH2:32][CH:33]([OH:36])[CH2:34][OH:35])=[O:15])[C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cc(C(=O)O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: NCC(O)CO
Agent: Cl
Product: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cc(C(=O)NCC(O)CO)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 87 %

Procedure:
Reaction of the crude acid chloride made as above from acid 8 (2.9 g, 6.15 mmol) was dissolved in Me2CO (100 mL), cooled in an ice-bath and treated with an excess of 3-amino-1,2-propanediol. After string for 10 min. the reaction mixture was acidified to pH 2-3 with 1 N HCl, most of the solvent was evaporated, and the residue was partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc and the combined organic phases were dried and evaporated. The residue was adsorbed directly onto silica gel and chromatographed, elution with EtOAc/MeOH (from 50:1 to 10:1) giving 2-(5-{[(2,3-dihydroxypropyl)amino]carbonyl}{2-[(methylsulfonyl)oxy]ethyl}-2,4-dinitroanilino)ethyl methanesulfonate (9c) (2.92 g, 87%) as a yellow oil;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1.C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:18][C:19]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[N:9]=[CH:10][C:11]=12
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(Cn2nccc2N)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1O
Temperature: 120 °C
Yield: 122.2 %

Procedure:
A mixture of 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (3 g, 10 mmol) and (ethoxymethylene)propanedioic acid, diethyl ester (3.8 g, 18 mmol) was heated at 120° C. for 1.5 h, then allowed to cool. After cooling, the mixture was concentrated and the resulting residue was purified with CombiFlash® eluting with 0-30% EtOAc in hexanes to give an intermediate, LCMS (M+H): 374.1. The intermediate was dissolved in diphenyl ether (5 mL). The resulted solution was heated at 240° C. in microwave reactor for 1 h 20 min. After cooling, the solid crashed out was filtered and washed with hexanes to afford 4.0 g (80%) of the sub-title compound. LCMS calc. for C17H18N3O4 (M+H)+: m/z=328.1. Found: 328.1.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[C:6](=[O:39])[N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][S:20]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[N:22]CC4C=CC(OC)=CC=4)=[O:21])=[O:18])=[CH:12][C:11]=3[CH3:38])[C:8](=[O:9])[C:4]=2[CH:3]=1.O.[N+]([O-])([O-])=O.[NH4+]>O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>[Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[C:6](=[O:39])[N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][S:20]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[NH:22])=[O:21])=[O:18])=[CH:12][C:11]=3[CH3:38])[C:8](=[O:9])[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN=S(=O)(NC(=O)Nc2ccc(N3C(=O)c4ccc(Cl)cc4C3=O)c(C)c2)c2ccccc2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Product: Cc1cc(NC(=O)NS(=N)(=O)c2ccccc2)ccc1N1C(=O)c2ccc(Cl)cc2C1=O

Procedure:
To 10 mg (0.016 mmol) of {[4-(5-chloro-1,3-dioxobenzo[c]azolidin-2-yl)-3-methylphenyl]-amino}N-(N-p-methoxybenzylphenylsulfonimidoyl)carboxamide dissolved in 380 μL of CAN followed by 96 uL of water was added 70 mg (0.13 mmol) of cerric ammonium nitrate. After 20 m, the reaction was complete and purified by RP-HPLC to give 1.8 mg (23%) after lyophilization. ES-MS (M+H)+=469 (Cl).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[C:11](=[N:19][OH:20])[CH2:12][CH2:13][N:14]([CH3:18])[S:15](=[O:17])(=[O:16])[C:9]=2[CH:8]=[CH:7]1.Cl.[F:22][C:23]1[CH:36]=[CH:35][C:26]([C:27]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+].[I-].[Na+]>C(#N)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[C:11](=[N:19][OH:20])[CH2:12][CH2:13][N:14]([CH3:18])[S:15](=[O:17])(=[O:16])[C:9]=4[CH:8]=[CH:7]3)[CH2:31][CH2:30]2)=[O:28])=[CH:35][CH:36]=1
Reactant: CN1CCC(=NO)c2c(ccn2CCCCCl)S1(=O)=O
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: CN1CCC(=NO)c2c(ccn2CCCCN2CCC(C(=O)c3ccc(F)cc3)CC2)S1(=O)=O
Yield: 64.7 %

Procedure:
A suspension of 110 mg (0.34 mmol) of Compound 21, 83 mg (0.34 mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride, 114 mg (1.36 mmol) of sodium hydrogencarbonate and 102 mg (0.68 mmol) of sodium iodide in 10 ml of acetonitrile was refluxed for 17 hours. Post-treatment was conducted in a similar manner as in Example 18. The residue was purified by chromatography on a silica gel column (eluent:methanol/chloroform=11/189), whereby 108 mg of the title compound were obtained tained (yield: 64%).
Reaction SMILES: C([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22]([O:26][CH3:27])[S:21]4)[O:17][C:13]=2[CH:12]=[C:11]([Cl:28])[CH:10]=1)C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1.B(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O.O>[Cl:28][C:11]1[CH:12]=[C:13]2[O:17][C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22]([O:26][CH3:27])[S:21]4)=[CH:15][C:14]2=[C:9]([OH:8])[CH:10]=1
Reactant: COc1nn2cc(-c3cc4c(OCc5ccccc5)cc(Cl)cc4o3)nc2s1
Agent: Cc1cc(C)c(C)c(C)c1C
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1nn2cc(-c3cc4c(O)cc(Cl)cc4o3)nc2s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
A stirred solution of 6-(4-(benzyloxy)-6-chlorobenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole (Example 37H, 0.85 g, 2.064 mmol) and pentamethylbenzene (2.142 g, 14.45 mmol) in DCM under N2 atmosphere was cooled to −78° C. after which boron trichloride (5.16 mL, 5.16 mmol) was added dropwise over ˜4 minutes. The reaction was monitored by TLC using 1:1 hexanes:EtOAc as eluent. The reaction mixture was stirred at −78° C. for 30 minutes after which a mixture of water (40 mL) and saturated NaHCO3 (5 mL) was added (at −78° C.) and the mixture was stirred until ambient temperature was obtained (removed from cooling bath). The solid precipitate was filtered off and rinsed with diethyl ether then allowed to dry overnight to give the title material (441 mgs, 1.371 mmol, 66.4% yield) as a beige solid. The filtrate was extracted with DCM. The organic phase was washed with brine, dried (MgSO4) and concentrated to dryness. The residue was purified by ISCO using DCM/EtOAc as eluent Fractions containing the desired product were concentrated to give the title material (25 mgs, 0.078 mmol, 3.77% yield) as a beige solid. LC (Method A): 2.167 min. LCMS (APCI) calcd for C13H9ClN3O3S [M+H]+ m/z 322.00, found 322.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 10.50 (br. S, 1H), 8.45 (s, 1H), 7.17 (dd; J=0.8, 1.6 Hz, 1H), 7.09 (d, J=0.8 Hz, 1H), 6.67 (d, J=2.0 Hz, 2H), 4.21 (s, 3H).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].N1C=CN=C1.Cl[Si:13]([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.O>[CH3:14][Si:13]([CH3:16])([CH3:15])[O:6][CH2:1][CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCCCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: C#CCCCO[Si](C)(C)C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of 4-pentyn-1-ol (25.0 g, 0.30 mole) in dry CH2Cl2 (250 ml) at 0° C., was added imidazole (40.46 g, 0.60 mole) and chlorotrimethylsilane (56.6 ml, 0.45 moles) and stirred for 2 h. The reaction mixture was diluted with water and extracted with CH2Cl2 (3×100 ml). Combined organic extracts were washed with water, brine, dried (Na2SO4) and the solvent was evaporated. Purification of the crude product by vacuum distillation afforded the pure ether 13 (44.1 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH:12]([F:14])[F:13])[CH:3]=1.[CH2:15](O)[CH:16]([OH:19])[CH2:17][CH3:18]>>[F:14][CH:12]([F:13])[O:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1([CH3:9])[O:19][CH:16]([CH2:17][CH3:18])[CH2:15][O:10]1
Reactant: CCC(O)CO
Reactant: CC(=O)c1ccc(Cl)cc1OC(F)F
Product: CCC1COC(C)(c2ccc(Cl)cc2OC(F)F)O1
Temperature: 25 °C

Procedure:
12.8 parts of 1-(4-chloro-2-difluoromethoxyphenyl)ethan-1-one and 10.4 parts of 1,2-butanediol are heated under reflux for 12 hours in 100 ml of abs. toluene in the presence of 0.2 part of p-toluene-sulfonic acid as catalyst, while removing the water of reaction with a water separator. The reaction mixture is cooled to room temperature and then washed with 2×100 ml of water, dried over sodium sulfate and filtered. The solvent is removed by evaporation and the residual oil is purified by high-vacuum distillation; b.p. 78°-80° C./0.04 mbar.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:14](=[O:15])[N:13]([C:16]4[CH:24]=[C:23]5[C:19]([CH:20]=[CH:21][N:22]5[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[CH:18][CH:17]=4)[CH2:12][C:5]=3[N:6]([CH3:11])[C:7]=2[CH:8]=[CH:9][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:4]3[C:14](=[O:15])[N:13]([C:16]4[CH:24]=[C:23]5[C:19]([CH:20]=[CH:21][N:22]5[CH2:25][C:26]([OH:28])=[O:27])=[CH:18][CH:17]=4)[CH2:12][C:5]=3[N:6]([CH3:11])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Cn1c2c(c3c(Cl)cccc31)C(=O)N(c1ccc3ccn(CC(=O)OC(C)(C)C)c3c1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c2c(c3c(Cl)cccc31)C(=O)N(c1ccc3ccn(CC(=O)O)c3c1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 2-(6-(8-chloro-4-methyl-1-oxopyrrolo[3,4-b]indol-2(1H,3H,4H)-yl)-1H-indol-1-yl)acetate (1.6 mmol, 1 equiv.) was dissolved in DCM (40 ml); TFA (16 ml) was added and the mixture was stirred for 2 h at 25° C. The solvent was reduced under reduced pressure, dichloromethane was added 2× to the residue, and in each case concentration to dryness again was carried out. The residue was used in the next step without being purified further.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH:9]([P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:6][CH:5]=1)([O-])=O.O.NN>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:26][CH:27]=1
Reactant: CCOP(=O)(OCC)C(Oc1ccc([N+](=O)[O-])cc1)P(=O)(OCC)OCC
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CO
Product: CCOP(=O)(OCC)C(Oc1ccc(N)cc1)P(=O)(OCC)OCC
Reaction time: 3 h

Procedure:
A solution of tetraethyl (4-nitrophenoxymethylene)-bisphosphonate (11 g) in methanol (120 ml) in a nitrogen atmosphere was cooled in ice and treated with hydrazine hydrate (5.3 ml) and 10% palladium on carbon (2.4 g). Stirring was continued for 3 hours at room temperature, and the catalyst was removed by filtration. The filtrate was evaporated in vacuo, and the crude product was purified by column chromatography on silica gel to give a colourless oil.
Reaction SMILES: C12(C3C=C(C=CC=3OC)C(O[C:17]3[CH:28]=[CH:27][C:20]([C:21]([O:23]CC=C)=[O:22])=[C:19]([CH3:29])[CH:18]=3)=O)CC3CC(CC(C3)C1)C2.C12(C3C=C(C=CC=3OC)C(OC3C=CC(C(O)=O)=C(C)C=3)=O)CC3CC(CC(C3)C1)C2>>[CH3:29][C:19]1[CH:18]=[CH:17][CH:28]=[CH:27][C:20]=1[C:21]([OH:23])=[O:22]
Reactant: C=CCOC(=O)c1ccc(OC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1C
Agent: COc1ccc(C(=O)Oc2ccc(C(=O)O)c(C)c2)cc1C12CC3CC(CC(C3)C1)C2
Product: Cc1ccccc1C(=O)O

Procedure:
In a manner analogous to Example 2(c), starting with 1.38 g (3 mmoles) of allyl 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-methylbenzoate, 780 mg of 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-methylbenzoic acid having a melting point of 236°-237° C. are obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13](=[O:20])[C:14]([N:18]=O)=[C:15]([NH2:17])[N:16]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)(=O)C>O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13](=[O:20])[C:14]([NH2:18])=[C:15]([NH2:17])[N:16]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccccc1-c1nc(N)c(N=O)c(=O)[nH]1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
2-(2-Allyloxyphenyl)-4-amino-5-nitrosopyrimid-6-one (6.3 g.) was suspended in a solution of triethylamine (15 ml.) in water (250 ml.). Sodium dithionite (12 g.) was added in portions with stirring at room temperature. The temperature of the mixture was then raised to 60° C., and it was stirred at this temperature for a further 20 minutes. The pH of the mixture was adjusted to 7 by the addition of glacial acetic acid, and the mixture cooled in ice/water. The solid was filtered off and washed with water to give 2-(2-allyloxyphenyl)-4,5-diaminopyrimid-6-one (5.1 g.), m.p. 127°-130° C.
Reaction SMILES: O[C:2]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:28]2([CH3:29])[C@H:13]([C@H:14]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:17]([CH2:18][C@H:19]([CH2:21][CH2:22]2)[OH:20])=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9])([CH3:4])[CH3:3].S(=O)(=O)(O)O.P(Cl)(Cl)(Cl)=O>>[CH3:9][C@@H:8]([C@@H:10]1[C@@:28]2([CH3:29])[CH2:27][CH2:26][C@@H:25]3[C@@:23]4([CH3:24])[CH2:22][CH2:21][C@H:19]([OH:20])[CH2:18][C:17]4=[CH:16][CH2:15][C@H:14]3[C@@H:13]2[CH2:12][CH2:11]1)[CH2:7][CH2:6][CH:5]=[C:2]([CH3:3])[CH3:4]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=S(=O)(O)O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
As the starting material, which is converted to 25-hydroxycholesterol by Grignard reaction, and then dehydrated in the presence of sulfuric acid or phosphorus oxychloride to provide desmosterol or an ester thereof (see J. Org. Chem. 23, p. 459, and J. Lipid Research, 8, p. 152). This method however again has such deficiencies as that the starting 25-ketonorcholesterol is expensive and that the yield of dehydration reaction is low. Particularly when phosphorus oxychloride is used in the reaction, substantial amounts of 25-dehydrocholesterol 3-acetate is produced as a by-product. Thus, the method is not industrially advantageous.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3.C(O)C.[OH-].[K+].[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)([F:26])([F:25])[F:24]>O>[F:24][C:23]([F:26])([F:25])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3
Reactant: FC(F)(F)CCCCCBr
Reactant: O=c1c2ccc(O)cc2oc2cc(O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=c1c2ccc(O)cc2oc2cc(OCCCCCC(F)(F)F)ccc12
Reaction time: 2 h

Procedure:
To 3,6-dihydroxy-xanthone (0.58 g, 1 equivalent) is added 10 ml of ethanol, then 117 mg of KOH 0.8 equivalents), followed by 0.58 g of CF3(CH2)5Br (1 equivalent); after two hours of boiling this mixture, the pH had dropped to the acidic range, and another 100 mg of KOH was added and heating continued overnight. The cooled mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml), the combined extracts washed with 5 ml of water and brought to dryness. Separation of the 3-component mixture was achieved by chromatography (100 g of silica gel, column diameter 5 cm) with solvents of increasing polarity: Solvents used: ethyl acetate (A), hexane (isomeric mixture) (B), ethanol (C)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:26]=[CH:25][N:24]([CH3:27])[N:23]=2)=[N:10]1.Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH:30]1[C:35]([OH:37])=[O:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[N:26]=[CH:25][N:24]([CH3:27])[N:23]=2)[NH:12][C:13]([CH2:20][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[C:35]([OH:37])=[O:36])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncn(C)n2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncn(C)n2)=NC1c1ccc(F)cc1Br
Yield: 45.3 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1-methyl-1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (0.5 g, 1 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.17 g, 1 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.25 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:20]O>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:20])=[O:8]
Reactant: Cc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1C
Yield: 35 %

Procedure:
A solution of crude 5-chloro-2-methyl-3-nitrobenzoic acid (13.2 g) in dry methanol (100 mL) was cooled to 0° C. (3 mL) was added conc. H2SO4 dropwise. After the addition, the mixture was heated to reflux for 16 hr. After removal of solvents under reduced pressure, the crude product was purified by silica gel chromatography (petroleum ether to petroleum ether/EtOAc=50:1) to give the title compound (6.3 g, yield 35% for two steps) as a white solid. LC-MS (ESI) m/z: 230 (M+1)+, 231 (M+2)+. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.59 (s, 3H), 3.95 (s, 3H), 7.84-7.85 (d, 1H), 7.98-7.99 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:67][C:68]1[CH:81]=[CH:80][C:71]([C:72]([N:74]2[CH2:78][CH2:77][C@@H:76]([NH2:79])[CH2:75]2)=[O:73])=[CH:70][CH:69]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:67][C:68]1[CH:81]=[CH:80][C:71]([C:72]([N:74]2[CH2:78][CH2:77][C@@H:76]([NH:79][C:2]3[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=3)[CH2:75]2)=[O:73])=[CH:70][CH:69]=1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Reactant: N[C@@H]1CCN(C(=O)c2ccc(Cl)cc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cc1
Temperature: 90 °C
Yield: 63.3 %

Procedure:
To a solution of ethyl (2E)-3-(4-bromophenyl)acrylate (300 mg) in toluene (3 mL) was added palladium(II) acetate (26.4 mg), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (110 mg), cesium carbonate (583 mg), and (3R)-1-(4-chlorobenzoyl)-3-pyrrolidinamine (291 mg). The mixture was heated at 90° C. for 2 days. The resulting mixture was poured into sat.NH4Cl aq solution and extracted with AcOEt. The organic layer was washed with sat. NH4Cl ag solution, water, and brine, and dried over Na2SO4. The solvent was removed in vacuo and residual brown oil was purified by preparative thin layer chromatography (chloroform methanol=95:5) to give ethyl (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)acrylate (297 mg) as pale yellow form.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][CH:21]=[CH:22][C:15]=23)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[N:11]1([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][CH:21]=[CH:22][C:15]=23)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: c1ccc(CN2CCN(c3ccnc4[nH]ccc34)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: c1cc(N2CCNCC2)c2cc[nH]c2n1

Procedure:
A solution of 4-(4-benzyl-piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (3.90 g, 13.3 mmol) and Pd(OH)2/C (937 mg, 1.33 mmol) in MeOH (60 mL) was stirred under 1 atmosphere of H2 for 2 d. The mixture was diluted with MeOH, filtered through diatomaceous earth, and the filtrate was concentrated in vacuo to give 4-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine as a solid (100 mg kept as free base). The remaining material was suspended in MeOH and treated with 2.0 M HCl in Et2O. This mixture was concentrated in vacuo to give 4-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine dihydrochloride (2.30 g). 1H NMR (DMSO-d6, 400 MHz) δ 11.5 (bs, 1H), 9.43 (bs, 2H), 7.96 (d, J=5.4 Hz, 1H), 7.25 (d, J=3.3 Hz, 1H), 6.49 (d, J=3.4 Hz, 1H), 6.45 (d, J=5.4 Hz, 1H), 3.56 (bs, 4H), 3.21 (bs, 4H).
Reaction SMILES: C(O)C.[OH-].[Na+].[CH3:6][C:7]([CH:14]=[CH:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:8][C:9]([O:11]CC)=[O:10]>O>[CH3:6][C:7]([CH:14]=[CH:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C=C(C)C=CCC(C)CCCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C=CCC(C)CCCC(C)C)=CC(=O)O
Yield: 58 %

Procedure:
To 350 ml. of ethanol, 105 ml. of water and 70 ml. of 50% aqueous sodium hydroxide is added 46.5 g. of ethyl 3,7,11-trimethyldodeca-2,4-dienoate (40% cis, trans and 60% trans,trans). The mixture is refluxed for about 19 hours. After cooling, ethanol is removed under reduced pressure and water added followed by extraction with ether to yield 3,7,11-trimethyldodeca-2,4-dienoic acid containing about 58% trans,trans isomer. Conversion of the thus-obtained acid to the benzylisothiouronium salt recrystallized from aqueous methanol, and regeneration of the acid with ether-aqueous hydrochloric acid provides crystalline trans,trans 3,7,11-trimethyldodeca-2,4-dienoic acid.