Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13][N:14]=[N+:15]=[N-:16])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Li+]>>[N:14]([CH2:13][CH2:12][CH2:11][CH2:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][CH2:8][CH2:9]1)=[N+:15]=[N-:16]
Reactant: COC(=O)C1(CCCCN=[N+]=[N-])CCCC1
Agent: [Li+]
Agent: [OH-]
Product: [N-]=[N+]=NCCCCC1(C(=O)O)CCCC1

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 3, starting from 1-[4-azidobutyl]cyclopentanecarboxylic acid methyl ester and lithium hydroxide.
Reaction SMILES: Cl.[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:16]1[CH:38]=[CH:37][C:19]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)C(=O)CC(OC)=O)([CH3:4])[CH3:3].[Cl-].COC(=O)CC(O)=O>>[CH:2]([O:5][CH2:6][CH2:7][NH:8][C:16]1[CH:38]=[CH:37][C:19]([C:20]([N:22]2[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[CH2:26][CH2:27]2)=[O:21])=[CH:18][CH:17]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)CC(=O)N(CCOC(C)C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: COC(=O)CC(=O)O
Agent: Cl
Agent: [Cl-]
Product: CC(C)OCCNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
In a manner analogous to that described in Example 23, 1-{4-[N-(2-isopropyloxyethyl)-N-methoxycarbonylacetylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine hydrochloride having a melting point of 77°-79° is obtained from 1 g of 1-{4-[N-(2-isopropyloxyethyl)amino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine (Example 1) by reaction with malonic acid monomethyl ester chloride.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[OH-].[Na+:38]>O>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O-:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[Na+:38]
Reactant: CC(C)(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A suspension of the product of Example 48H in water (3 mL) was treated with 0.997N sodium hydroxide solution (0.410 mL) and stirred at 25° C. for 1 hour. The solution was lyophilized to give 209 mg (74%) of a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 0.43 m, 1 H) 0.70 (s, 9 H) 0.81 m, 1 H) 1.38 (s, 3 H) 1.71 m, 1 H) 2.16 (m, 1 H) 2.90 (s, 3H) 7.28 m, 3 H) 7.44 m, 3 H) 8.05 (d, J=7.35 Hz, 1 H) 9.87 (s, 1 H) 15.44 (s, 1 H); MS (ESI−) m/z 530 (M−H)−.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:42])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH:20]=[CH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4Br)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:30])[C:12]=2[C@H:31]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(#N)C>[C:38]([O:37][C@@H:31]([C:12]1[C:13]([CH3:30])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:42])([O:4][CH2:1][CH:2]=[CH:3][C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH:21]=[CH:20]3)[CH2:6][CH2:7]1)[C:32]([O:34][CH2:35][CH3:36])=[O:33])([CH3:40])([CH3:41])[CH3:39]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(C=CCc4ccccc4Br)nn23)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=Cc1ccccc1CC=C3
Temperature: 120 °C
Yield: 51.8 %

Procedure:
To a pressure tube flushed with N2 were added (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-(2-bromophenyl)prop-1-en-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.09 g, 0.141 mmol), acetonitrile (4 ml) and triethylamine (0.196 ml, 1.407 mmol). Added to this solution were triphenylphosphine (0.011 g, 0.042 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.013 g, 0.014 mmol). The tube was sealed and stirred at 120° C. After stirring for 20 h, the mixture was cooled, filtered and concentrated to give a yellow residue. The residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 20 CV) to give the title compound (0.0406 g, 0.073 mmol, 51.6% yield) as a sticky yellow oil. LCMS (M+H) calcd for C33H43N4O4: 559.32. found: 559.5.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:36])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].[CH2:42](N(CC)CC)C.O>C(Cl)Cl>[F:36][C:3]1[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([Si:26]([CH:30]([CH3:32])[CH3:31])([CH:33]([CH3:35])[CH3:34])[CH:27]([CH3:28])[CH3:29])[CH:12]=2)=[O:10])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:38]([CH2:37][CH3:42])(=[O:40])=[O:39]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(=O)c2c(F)ccc(N)c2F)c2cc(-c3cccnc3)cnc21
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncc(-c4cccnc4)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (3-amino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (57, 35.0 mg. 0.069 mmol) in methylene chloride (6 mL) was added methanesulfonyl chloride (0.30 mL, 3.9 mmol) and triethylamine (0.40 mL, 2.9 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude compound that was used in the next step.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]12([C:21]3[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][C:22]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2>N1C=CC=CC=1>[C:11]12([C:21]3[CH:29]=[CH:28][C:24]([C:25]([S:1][C:2]4[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=4)=[O:26])=[CH:23][C:22]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:12][CH:13]3[CH2:14][CH:15]([CH2:16][CH:17]([CH2:19]3)[CH2:18]1)[CH2:20]2
Reactant: COCCOCOc1cc(C(=O)Cl)ccc1C12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1ccc(S)cc1
Solvent: c1ccncc1
Product: COCCOCOc1cc(C(=O)Sc2ccc(C(=O)O)cc2)ccc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
850 mg (5.5 mmol) of 4-mercaptobenzoic acid and 20 ml of pyridine were introduced into a round-bottomed flask. A solution of 2.08 g (5.5 mmol) of 4-(1-adamantyl)-3-methoxyethoxymethoxybenzoyl chloride prepared above was added dropwise and the mixture was stirred at room temperature for six hours. It was evaporated to dryness and the residue was taken up in water and ethyl acetate and acidified to pH 5, and the organic phase was separated out after settling had taken place, washed with water, dried over magnesium sulfate and evaporated. The solid obtained was purified by chromatography on a column of silica, eluted with a mixture of dichloromethane and methanol (98/2). 1.5 g (57%) of 4-[4-(1-adamantyl)-3-methoxyethoxymethoxybenzoylthio]benzoic acid, having a melting point of 219°-21° C., was recovered.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1.NC[C@H](O)C>>[CH3:1][C@@H:2]1[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1
Reactant: C[C@@H]1CNC(=O)c2cc3ccc(C(=O)O)cc3n21
Agent: C[C@@H](O)CN
Product: C[C@H]1CNC(=O)c2cc3ccc(C(=O)O)cc3n21

Procedure:
This compound is synthesized using the similar procedure used to prepare (4R)-4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylic acid (Intermediate C), replacing (2S)-1-aminopropan-2-ol with (2R)-1-aminopropan-2-ol in Step 1.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH3:8].C(O)(C(F)(F)F)=O.C(=O)([O-])[O-]>C(Cl)Cl>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C@H:6]([NH2:9])[CH2:7][CH3:8]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1nnco1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](N)c1nnco1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 72 %

Procedure:
tert-butyl N-[(1R)-1-(1,3,4-oxadiazol-2-yl)propyl]carbamate (2.255 g, 9.923 mmol) was dissolved in DCM (17.76 mL) at 0° C. and TFA (17.76 mL) was added. The reaction was stirred at 0° C. for 4.5 hours then concentrated under high vacuum. The residue was azeotroped with DCM (×2). The resultant oil was dissolved in a mixture of THF (40 ml) and DCM (20 ml) then treated with MP-carbonate (15 g, 199.9 mmol). The reaction was stirred gently for 1 hour then filtered. The resin was stirred with further portions DCM (2×25 ml) and filtered. The combined filtrates were filtered and concentrated to give the sub-title compound as a colourless oil (908 mg, 72%); 1H NMR (400.0 MHz, DMSO) d 0.86 (3H, t), 1.61-1.80 (2H, m), 2.23 (2H, br hump), 3.98 (1H, m), 9.15 (1H, s); MS ES (+) 128.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16](C)[C:15]3=[O:20])[CH:7]=[N:6]1.NC1C(C(NC)=O)=C([F:61])C(C2C=NN(CCCO)C=2)=CC=1>>[F:61][C:18]1[C:14]([C:15](=[O:20])[NH:16][CH3:17])=[C:13]([NH:21][C:22]2[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]3[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=3[O:48][CH3:49])[N:23]=2)[CH:12]=[CH:11][C:10]=1[C:8]1[CH:7]=[N:6][N:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:9]=1
Reactant: CNC(=O)c1c(N)ccc(-c2cnn(CCCO)c2)c1F
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c(F)c3C(=O)NC)n2)c(OC)c1)OCC
Yield: 30 %

Procedure:
Prepared analogously to Compound 1B replacing compound 1C with 6-amino-2-fluoro-3-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylbenzamide (281 mg, 961 μmol) to afford 204 mg of the title compound (30%). 1H NMR (400 MHz, CD3OD) δ=8.32 (s, 1H), 8.15 (d, J=1.8 Hz, 1H), 7.94-8.01 (m, 2H), 7.89 (d, J=8.1 Hz, 1H), 7.73 (t, J=8.6 Hz, 1H), 6.98 (t, J=2.0 Hz, 1H), 6.77 (d, J=8.1 Hz, 1H), 4.32 (t, J=7.0 Hz, 2H), 3.97-4.07 (m, 4H), 3.89 (s, 3H), 3.55-3.60 (m, 2H), 3.24 (s, 1H), 3.19 (s, 1H), 2.91 (s, 3H), 2.10 (quin, J=6.5 Hz, 2H), 1.23 (t, J=7.1 Hz, 6H). MS (ESI): m/z=710.21 [M+H]+. UPLC: tR=1.39 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:24][C:25]([F:28])([F:27])[F:26])=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)[CH2:35][CH2:34]1)(=[O:32])=[O:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:22])[NH:46][C:43]3[CH:44]=[CH:45][C:40]([CH2:39][N:36]4[CH2:35][CH2:34][N:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:38][CH2:37]4)=[CH:41][CH:42]=3)=[CH:17][CH:16]=2)[C:12]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)O)cc2)c1
Reactant: CS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(S(C)(=O)=O)CC4)cc3)cc2)c1
Reaction time: 16 h

Procedure:
A mixture of 5′-tert-butoxycarbonylamino-2′-trifluoromethoxy-biphenyl-4-carboxylic acid (50 mg), 4-(4-methanesulfonyl-piperazin-1-ylmethyl)-phenylamine (35.2 mg), HBTU (49.6 mg) and N-Methylmorpholine (30 ul) in dry DMF (3 ml) was stirred for 16 hrs.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:49])[CH2:18][NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:41][CH2:40][CH2:39]3)=[O:30])[N:24]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:23]=2)=[O:21])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[O:49]=[C:17]([N:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)[CH2:18][NH:19][C:20]([C:22]1[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@H:32]2[C:36](=[O:42])[NH:37][CH:38]2[CH2:39][CH2:40][CH2:41]2)=[O:30])[N:24]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:23]=1)=[O:21]
Reactant: O=C(NCC(=O)N1CCN(C(=O)OCc2ccccc2)CC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: [Pd]
Solvent: CCO
Product: O=C(NCC(=O)N1CCNCC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reaction time: 12 h

Procedure:
A suspension of 2.5 g 4-[2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-acetyl]-piperazine-1-carboxylic acid benzyl ester and 0.5 g Pd/C (10%) in 100 ml ethanol was stirred under an atmosphere of hydrogen (3 bar) for 12 h. The mixture was filtrated over a plug of Celite, washed with ethanol and the combined wash solutions concentrated to give the title compound as colourless oil. Yield: 2.3 g.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[F:16][CH:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1>>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[C:5]([O:7][CH:17]([F:16])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:19]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: FC(Br)c1cccc(Oc2ccccc2)c1
Product: CC(C)C(C(=O)OC(F)c1cccc(Oc2ccccc2)c1)c1ccc(Cl)c(Cl)c1

Procedure:
This compound was prepared from α-isopropyl-(3,4-dichlorophenyl)acetic acid and α-fluoro-3-phenoxybenzyl bromide following the procedure described in Example 2 Method B. The product, a colourless oil, was characterised by pmr spectroscopy. Chemical shift δ ppm (solvent CDCl3): 0.76(3H, d, J=6Hz, CH3); 1.07(3H, d of d, J=6Hz and J=2Hz, CH3); 2.33(1H, m, --CH(CH3)2); 3.28(1H, d, J=10Hz, CH); 7.24(1H, d of d, J=56Hz and J=2Hz, CHF) and about 7.33(12H, m, aromatic protons).
Reaction SMILES: O=O.[K+].Br[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)=[O:10].C1OCCOCCOCCOCCOCC[O:23]C1.O>CS(C)=O>[OH:23][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)=[O:10]
Reactant: O=C(CCCCBr)N1CCCc2ccccc21
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: O=O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(CCCCO)N1CCCc2ccccc21

Procedure:
Potassium superoxide (0.50 g) was added to a solution of 1-(5-bromopentanoyl)-1,2,3,4-tetrahydroquinoline (1.8 g) and 18-Crown-6 (0.4 g) in dimethylsulfoxide (25 ml). After 8 hours the solution was added to water and extracted with ether. The extract was washed, dried and evaporated and the residue was chromatographed on silica gel, eluting with 95:5 methylene chloride:methanol, to yield 1-(5-hydroxypentanoyl)-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Na].[CH2:10]([O:28][C:29]1[O:33][CH:32]=[C:31]([C:34](Cl)=[O:35])[CH:30]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1C=CC=CC=1>[CH2:10]([O:28][C:29]1[O:33][CH:32]=[C:31]([C:34]([CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH3:8])=[O:6])=[O:35])[CH:30]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCC/C=C\CCCCCCCCOc1cc(C(=O)Cl)co1
Reactant: COC(=O)CC(C)=O
Agent: [Na]
Solvent: c1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCOc1cc(C(=O)C(C(C)=O)C(=O)OC)co1

Procedure:
To a cooled mixture of 40.0 g (0.106 mole) of 5-(cis-9-octadecen-1-yloxy)-3-furoic acid in methylene chloride is added 30 ml of thionyl chloride. The mixture is stirred for 5 hours. Then the solvent and excess thionyl chloride is removed under reduced pressure affording the crude 5-(cis-9-octadecen-1-yloxy)-3-furoyl chloride. A mixture of 11.6 g (0.100 moles) of methyl acetoacetate and 2.3 g of sodium in 1 liter of benzene is refluxed for 20 hours, then cooled, and the crude 5-(cis-9-octadecen-1-yloxy)-3-furoyl chloride is added over a two hour period. The mixture is refluxed for 6 hours, cooled by the addition of ice and mixed well. The benzene layer is separated, washed with 5% sodium bicarbonate solution and dried. The benzene is distilled off under reduced pressure yielding 2-[5-(cis-9-octadecen-1-yloxy)-3-furoyl]acetoacetic acid, methyl ester. To a solution of 3.3 g of ammonium chloride in 15 ml of water at 40° C is added 10 g of the above ester maintaining the temperature at 40° C for 15 minutes followed by rapid cooling. The solution is extracted with ether, the extract dried, and evaporated to dryness affording 2-[5-(cis-9-octadecen-1-yloxy)-3-furoyl]acetic acid methyl ester.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=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-].[K+].[K+]>O1CCOCC1.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>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH:15]([CH3:17])[CH3:16])=[CH:20][CH:21]=2)[CH:11]=1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(Cl)cc(-c3ccc(OC(C)C)cc3)nc2c1
Temperature: 90 °C
Yield: 85.1 %

Procedure:
To a degassed solution of 2,4-dichloro-7-methoxyquinoline (1 g, 4.3 mmol) in dioxane/water (8:2) was added 4-isopropoxyphenylboronic acid (870 mg, 4.82 mmol) followed by potassium carbonate (1.2 g, 8.7 mmol) and Pd(PPh3)4 (253 mg, 0.22 mmol) at room temperature under nitrogen atmosphere. The reaction mass was heated at 90° C. for 18 h. The solvent was removed under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to afford 4-chloro-2-(4-isopropoxyphenyl)-7-methoxyquinoline (1.2 g, 85%) as off white solid. MS: MS m/z 328.7 (M++1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][N:3]=1.[C:12](O)(=O)[CH2:13][CH3:14].P(=O)(O)(O)O.[OH-].[Na+]>>[CH2:13]([C:14]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][C:6]=2[CH2:9][CH2:10][CH3:11])[CH3:12]
Reactant: CCCc1ccnc(N)c1N
Reactant: CCC(=O)O
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCc1ccnc2nc(CC)[nH]c12
Temperature: 25 °C

Procedure:
2.6 g (0.017M) of 2,3-diamino-4-n-propylpyridine and 1.4 ml (0.019M) of propionic acid were added to 15 ml of phosphoric acid, and the mixture was heated at 140° to 150° C. for 20 hr. It was cooled to room temperature, poured into a cold aqueous NaOH solution and then extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off in vacuo to prepare a substantially pure brown oleaginous intended product. The yield was 2.9 g (this compound was used as a starting material in the preparation of the following raw material (29)).
Reaction SMILES: C(Br)C.[Mg].[OH:5][C:6]([CH3:16])([CH:9]=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=[CH2:14])[C:7]#[CH:8].[CH3:17][C:18]1([CH3:26])[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[C:19]1=[O:25].[Cl-].[NH4+]>C(OCC)C.C1C=CC=CC=1>[OH:5][C:6]([CH3:16])([C:7]#[C:8][C:19]1([OH:25])[CH:20]([CH3:24])[CH2:21][CH2:22][CH2:23][C:18]1([CH3:26])[CH3:17])[CH:9]=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=[CH2:14]
Reactant: C#CC(C)(O)C=CC=C(C)C=C
Reactant: CC1CCCC(C)(C)C1=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CCBr
Product: C=CC(C)=CC=CC(C)(O)C#CC1(O)C(C)CCCC1(C)C

Procedure:
A solution of ethyl bromide (1.75 g.) in diethyl ether was added to a suspension of magnesium (0.385 g.) in ether and the mixture was heated to reflux for 30 minutes. A solution of the alcohol, 3-hydroxy-3,7-dimethyl-nona-4,6,8-trien-1-yne, (1.0 g.) in dry benzene was added and the mixture refluxed 30 minutes. A solution of 2,2,6-trimethylcyclohexanone (1.12 g.) in benzene was added and the mixture refluxed for 15 minutes and poured into saturated aqueous ammonium chloride solution. The organic phase was washed with brine dried and concentrated to give 7-hydroxy-3,7-dimethyl-9-(1-hydroxy-2,2,6-trimethylcyclohexyl)-nona-1,3,5-trien-8-yne which was chromatographed on activity III alumina to give pure 7-hydroxy-3,7-dimethyl-9-(1-hydroxy-2,2,6-trimethyl-cyclohexyl)-nona-1,3,5-trien-8-yne.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[Cu][C:15]#[N:16].O.C(OCC)C>CN1CCCC1=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:15]#[N:16])=[CH:3][C:4]=1[C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: O=Cc1ccc(Br)cc1C(F)(F)F
Reactant: N#C[Cu]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc(C=O)c(C(F)(F)F)c1
Temperature: 200 °C
Reaction time: 3 h
Yield: 38.8 %

Procedure:
To a solution of 4-bromo-2-(trifluoromethyl)benzaldehyde (2.0 g) in N-methylpyrrolidin-2-one (39.5 mL) was added copper(I) cyanide (1.42 g). The reaction mixture was stirred at 200° C. for 3 hr, allowed to cool to room temperature, poured into water, and diethyl ether was added. The insoluble material was removed by filtration through celite. The organic layer of the filtrate was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.610 g).