Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([Cl:18])=[C:12]([F:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])C.C(=O)([O-])[O-].[K+].[K+].[F:25][CH2:26][CH2:27]I>CN(C=O)C>[Cl:18][C:11]1[CH:10]=[C:9]2[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]2[CH2:27][CH2:26][F:25])=[CH:13][C:12]=1[F:17]
Reactant: FCCI
Reactant: CCOC(=O)c1c[nH]c2cc(Cl)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(CCF)c2cc(Cl)c(F)cc2c1=O
Reaction time: 9.5 h
Yield: 69.4 %

Procedure:
To a stirred mixture of the above ester (1.35 g), potassium carbonate (1.73 g) and DMF (20 ml), 4.35 g of 2-fluoroethyl iodide was added and the mixture was stirred at 80° -90° C. for 9.5 hours. After the solvent evaporated off, the residue was extracted with dichromomethane, the dichloromethane layer was washed with water, and dried. The solvent was evaporated. The residue was added to 18% hydrochloric acid (20 ml) and refluxed for 3 hours. After the mixture cooled, the solid was filtered, washed with water, dried, and recrystallized from a mixture of DMF and ethanol to give 7-chloro-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.0 g).
Reaction SMILES: [C:1]([O:7][CH2:8][O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](Cl)=[O:16])=[O:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:32]([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH:44]([CH3:46])[CH3:45])[NH2:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:32]([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH:44]([CH3:45])[CH3:46])[NH:42][C:15](=[O:16])[C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][C@@H:12]([C:10]([O:9][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)C(=O)OCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)Cl
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)OCOC(=O)C(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Pivaloyloxymethoxycarbonyl)-2,4-(R*,R*)-dibenzylbutyryl chloride (1.2 g) in 10 ml of methylene chloride is added slowly to a solution of 0.60 g of (L)-leucine benzyl ester and 0.30 ml of triethylamine in 20 ml of methylene chloride. The reaction is stirred overnight at room temperature. The solution is washed with 2 N hydrochloric acid, then with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrted to give N-[4-pivaloyloxymethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl]-L-leucine benzyl ester.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[C:29]([CH3:36])[N:28]=1.C(=O)([O-])O.[Na+].COCCOC>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.O>[F:26][C:27]1[C:32]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)=[CH:31][CH:30]=[C:29]([CH3:36])[N:28]=1
Reactant: Cc1ccc(B(O)O)c(F)n1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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: COCCOC
Product: Cc1ccc(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c(F)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-6-methylpyridin-3-yl)boronic acid (233 mg), sodium hydrogen carbonate (253 mg) and tetrakis(triphenylphosphine)palladium (88 mg) were added to a deaerated mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 100° C. for 2 hr. The reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:3→1:4) to give the title compound as a colorless oil (yield 400 mg, 87%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH2:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[F:12][C:13]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:14]=1[CH2:15][O:16][C:17]1[C:18]2[N:19]([C:23]([C:27](O)=[O:28])=[C:24]([CH3:26])[N:25]=2)[CH:20]=[CH:21][CH:22]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[F:12][C:13]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:14]=1[CH2:15][O:16][C:17]1[C:18]2[N:19]([C:23]([C:27]([NH:8][CH:6]3[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C:2]([CH3:11])([CH3:1])[CH2:7]3)=[O:28])=[C:24]([CH3:26])[N:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18.8 mg (0.12 mmol) of 2,2,6,6-tetramethylpiperidine-4-amine were initially charged, and 32 mg (0.10 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid in 0.4 ml of DMF and 42 mg (0.13 mmol) of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU) in 0.2 ml of DMF were added. 20 mg (0.20 mmol) of 4-methylmorpholine were then added, and the reaction was stirred at RT overnight. The mixture was then filtered off and the filtrate was purified by preparative LC-MS (Method 12). The product-containing fractions were concentrated under reduced pressure. This gave 27 mg (59% of theory) of the target product.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=[O:13])[CH2:4][O:3]1.[Li+].[OH-]>C1COCC1.O>[CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])[CH2:4][O:3]1
Reactant: COC(=O)c1cccc(OC[C@@H]2COC(C)(C)O2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC[C@@H](COc2cccc(C(=O)O)c2)O1
Temperature: 40 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
To a solution of (R)-methyl 3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoate (8.5 g, 32 mmol) in THF (80 ml) was added a solution of LiOH (2.3 g, 96 mmol) in water (20 ml). The mixture was stirred for 15 hours at 40° C. The mixture was concentrated and diluted with saturated solution of Na2CO3 (50 ml), washed with ethyl acetate (50 ml×2), The aqueous layer was adjusted to pH=4 by addition of aqueous 3N HCl. The precipitate was collected by filtration and the filtered cake was dried in vacuo to obtain (R)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoic acid as a white solid, (5.8 g, 72% yield).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:14][CH2:15][CH:16]=[CH2:17])[CH2:10][CH2:11]C=C>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:18])[CH2:10][CH2:11][CH:17]=[CH:16][CH2:15][CH2:14]1
Reactant: C=CCCC(O)(CCC=C)c1cccc(F)c1F
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: OC1(c2cccc(F)c2F)CCC=CCC1
Temperature: 40 °C

Procedure:
In a 1L round-bottomed flask (t=g) was added 5-(2,3-difluorophenyl)nona-1,8-dien-5-ol (1.76 g, 6.98 mmol) in CH2Cl2 (600 mL) to give a colorless solution. Grubbs I (0.175 g, 0.209 mmol) was added, and the mixture was heated at 40° C. for 2 hours. TLC showed clean conversion to a more polar spot (some impurities from starting material remained). Combined with 68908-198 and concentrated to dryness and the residue was subject to purification up to 50% Et2O/hexane (twice). The major peak was pooled and concentrated to a light green oil (1.40 g, 89.2%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.25 (m, 1H), 7.08-7.00 (m, 2H), 5.90-5.80 (m, 2H), 2.60-2.48 (m, 2H), 2.21 (t, J=7.0 Hz, 2H), 2.10-1.98 (m, 2H), 1.90-1.75 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][C:13](=[O:15])[CH3:14])[CH:8]=[CH:9][C:10]=1[OH:11])([O:3][CH3:4])=[O:2].IC.[C:18](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][C:13](=[O:15])[CH3:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:18])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cc(CC(C)=O)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(CC(C)=O)ccc1OC
Yield: 99.9 %

Procedure:
A mixture of 1-(3-carbomethoxy-4-hydroxyphenyl)propan-2-one (3.0 g), iodomethane (5.0 g), potassium carbonate (7.0 g) was refluxed in acetone until tlc showed no starting material (~6 hours). The mixture was cooled, filtered and evaporated. The residue was partitioned between ether and water and the layers separated. The ether layer was dried (MgSO4) and evaporated to give the title compound (3.2 g). τ (CDCl3) 7.84 (3H, s), 6.35 (2H, s), 6.1 (3H, s), 3.05 (1H, d, J=8 Hz), 2.68 (1H, dd, J=8 Hz, J=2 Hz), 2.36 (1H, d, J=2 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13]([S:17](Cl)(=[O:19])=[O:18])[CH2:14][CH2:15][CH3:16]>N1C=CC=CC=1>[CH2:13]([S:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)(=[O:19])=[O:18])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)Nc1ccc(C(=O)O)cc1

Procedure:
In a manner similar to Preparation 9 react ethyl 4-aminobenzoate with 1-butanesulfonyl chloride and pyridine to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.CC(C)([O-])C.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][C:17]=2[N+:26]([O-:28])=[O:27])[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-methylpiperidin-4-ol (2.99 mmol, 344.4 mg) was added to a suspension of potassium tert-butoxide in THF (5 mL) and stirred at RT for 30 minutes. 2-fluoro-5-trifluoromethyl nitrobenzene (2.39 mmol, 500 mg) was then added and the reaction mixture was stirred an additional 5 h at RT, at which time LC-MS showed complete conversion to the desired product. The reaction mixture was concentrated and the dark brown residue was taken up in methylene chloride (25 mL). This was washed with water (3×20 mL), dried over sodium sulfate, filtered and concentrated to give the crude product as a yellow oil. Crude material (>90% purity) was taken to the next step without further purification LC-MS: 305.1 (M+H)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>O>[C:23]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COC(=O)C(C)(C)c1ccc(CN)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)c1ccc(CNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(4-aminomethylphenyl)-2-methylpropionate (29.4 g) and triethylamine (23.8 ml) indichloroethane (300 ml) was added dropwise acetyl chloride (11.1 ml) at 5° C. over 30 min. The mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=3:1, ethyl acetate) to give the title compound (23.47 g) as a pale-yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)=[C:13](\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[CH2:14][CH3:15])=[CH:8][CH:7]=1)=[O:4].[Na+].[I-].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.Cl>C1COCC1.CCOC(C)=O>[N:35]1([CH2:2][C:3]([O:5][C:6]2[CH:11]=[CH:10][C:9](/[C:12](/[C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:24][CH:23]=3)=[C:13](\[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)/[CH2:14][CH3:15])=[CH:8][CH:7]=2)=[O:4])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: CC/C(=C(\c1ccc(/C=C/C(=O)O)cc1)c1ccc(OC(=O)CCl)cc1)c1ccccc1
Reactant: C1COCCN1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC/C(=C(\c1ccc(/C=C/C(=O)O)cc1)c1ccc(OC(=O)CN2CCOCC2)cc1)c1ccccc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of compound 32 (100 mg, 0.22 mmol) in THF (4 mL) was added NaI (100 mg, 0.67 mmol) and the mixture stirred for 1 h. The reaction was cooled to 5° C. and a solution of morpholine (0.029 mL, 0.33 mmol) in THF (2 mL) was added over 1 h. After stirring for 1 h, the reaction was diluted with EtOAc (40 mL) and poured into a mixture of ice water (30 mL) and 0.1 N HCl (10 mL). The layers were separated and the organic layer was washed with brine (40 mL), dried (MgSO4) and concentrated. Et2O (8 mL) was added and the mixture was stirred for 2 h. The resulting solid was filtered, rinsed with Et2O and dried to afford the title compound, 31, as a yellow solid (68 mg, 61%). 1HNMR (400 MHz, DMSO-d6): δ 0.85 (t, 3H), 2.39 (q, 2H), 2.52 (br, 4H), 3.43 (br, 2H), 3.55 (br, 4H), 6.50 (d, J=15.9 Hz, 1H), 6.80 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 7.09-7.19 (m, 5H), 7.24 (d, J=8.1 Hz, 2H), 7.58 (d, J=15.9 Hz, 1H), 769 (d, J=8.1 Hz, 2H), 12.33 (br s, 1H); MS m/z 498 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:18][CH:19]([CH2:23][CH3:24])[C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][CH:19]([CH2:23][CH3:24])[C:20]([NH:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][OH:10])=[O:21]
Reactant: CCC(Cl)C(=O)Cl
Reactant: N[C@@H](CO)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(Cl)C(=O)N[C@@H](CO)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-phenylglycinol (2.00 g, 14.6 mmol) and triethylamine (2.03 mL, 14.6 mmol) in CH2Cl2 (100 mL) at 0° C. was slowly added 2-chlorobutyryl chloride (1.66 mL, 14.6 mmol). After 30 min, the reaction mixture was quenched with saturated aqueous NaHCO3 (30 mL) and extracted with CH2Cl2 (2×75 mL). The combined organic extracts were washed with 10% citric acid, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-70:30 to 0:100, to give the title compound. MS: m/z=242 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.FC1C=C(C2N=CC(CCC(N3CCCCC3)=O)=CC=2)C=CC=1.[H-].[Na+].[C:47]([O:51][C:52](=[O:55])[CH2:53]Br)([CH3:50])([CH3:49])[CH3:48]>CN(C=O)C>[C:47]([O:51][C:52](=[O:55])[CH2:53][NH:14][C:11]1[CH:12]=[N:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: Nc1ccc(-c2ccc(F)cc2)nc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C(CCc1ccc(-c2cccc(F)c2)nc1)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNc1ccc(-c2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 300 mg (1.59 mmol) of 6-(4-fluoro-phenyl)-pyridin-3-ylamine (prepared analogously as described in Example 76(a) and (b)) and 104 mg (2.39 mmol) of sodium hydride (55% in mineral oil) in DMF were stirred at room temperature for 30 min. Then 466.4 mg (2.39 mmol) of bromoacetic acid tert-butyl ester were added and the reaction mixture was stirred for 2 h at room temperature and for 5 h at 100° C. After evaporation, water and ethyl acetate were added. The organic phase was separated, dried and evaporated. Yield: 480 mg.
Reaction SMILES: O[C@H](CC1C=CC=CC=1)C(O)=O.[Br:13][C:14]1[CH:22]=[CH:21][C:20]2[NH:19][C:18]3[CH2:23][C@@H:24]([NH2:26])[CH2:25][C:17]=3[C:16]=2[CH:15]=1.C(N(C(C)C)CC)(C)C.Cl[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38]>C1(C)C=CC=CC=1>[CH:40]([O:39][C:37](=[O:38])[NH:26][C@@H:24]1[CH2:23][C:18]2[NH:19][C:20]3[CH:21]=[CH:22][C:14]([Br:13])=[CH:15][C:16]=3[C:17]=2[CH2:25]1)([CH3:42])[CH3:41]
Reactant: CC(C)OC(=O)Cl
Reactant: N[C@@H]1Cc2[nH]c3ccc(Br)cc3c2C1
Agent: O=C(O)[C@H](O)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(Br)cc3c2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
(S)-7-Bromo-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-ylamine(R)-2-hydroxy-3-phenylpropionic acid salt (60.00 g, 143.78 mmol) and diisopropylethylamine (50 mL, 296.12 mmol) are combined in toluene (165 mL). The reaction vessel is purged with nitrogen three times. The mixture is cooled to 0° C. with stirring and is held at that temperature for 30 min. A solution of isopropyl chloroformate (20.00 g, 163.20 mmol) in toluene (165 mL) is added at 0-5° C. over 10 min. The mixture is stirred at 5° C. for 10 min. HPLC shows 98.6% complete. The reaction is quenched with water (1 L) and ethyl acetate (480 mL). The mixture is filtered and the solid is washed with ethyl acetate (2×240 mL). The combined organic layer is washed with brine twice, dried (MgSO4), and filtered. The organic solvent is reduced to 50 mL. The mixture is cooled to 25° C. and tert-butyl methyl ether (50 mL) and ethyl acetate (50 mL) are added. An off-white solid is precipitated. The solid is filtered and washed with heptanes (100 mL). The solid is dried under vacuum at 50° C. for 4 h to give 44.4 g (90.3%) of a light brown solid.
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[Cl:16][C:17]1[CH:18]=[C:19]([O:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=[N:21][CH:22]=1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:29]1[CH2:28][CH2:27][CH:26]([CH2:25][CH2:24][O:23][C:19]2[CH:20]=[N:21][CH:22]=[C:17]([Cl:16])[CH:18]=2)[CH2:31][CH2:30]1)#[N:2]
Reactant: Clc1cncc(OCCC2CCNCC2)c1
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Product: CC(C)C(C#N)(CCCN1CCC(CCOc2cncc(Cl)c2)CC1)c1cccs1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 4-[2-(5-chloro-3-pyridyloxy)ethyl]piperidine. The physico-chemical data of the compound was as below.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[OH-:18].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:15])=[CH:9][C:10]([Cl:14])=[CH:11][C:12]=2[Cl:13])[N:5]=[CH:4][C:3]=1[C:16]([NH2:17])=[O:18]
Reactant: [OH-]
Reactant: N#Cc1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled concentrated sulfuric acid (10 ml) was added portionwise 5-amino-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carbonitrile (4.000 g, 13.9 mmol) over a period of 45 minutes. The reaction mixture was allowed to stir at room temperature for 1 hour after addition. The mixture was poured over ice with stirring and the solution was neutralized with 15% NaOH in ice-bath. Precipitate formed and was filtered to give 3.57 g of yellow solid. 1H NMR (CDCl3): 5.3(brs,2H), 5.6(brs,2H), 7.5(s,2H), 7.7(s,1H)ppm.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:16](=[O:18])[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]>ClCCl.CO>[Br:1][CH2:17][C:16]([C:11]1([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:18]
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCCC1
Reactant: BrBr
Solvent: CO
Solvent: ClCCl
Product: O=C(CBr)C1(c2ccc(Cl)c(Cl)c2)CCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of bromine (6.1 ml) in dichloromethane (50 ml) was added dropwise over 3 hours at 10°-15° C. under nitrogen to a stirred solution of 1-[1-(3,4-dichlorophenyl)cyclopentyl]ethanone (31.9 g) in a mixture of methanol (60 ml) and dichloromethane (10 ml), then the mixture was stirred at ambient temperature for 2.5 hours and poured into an excess of ice-water. The aqueous layer was separated and washed with dichloromethane 3×100 ml), then the combined organic solutions were washed with saturated aqueous sodium hydrogencarbonate solution (2×100 ml) and water (100 ml), dried over calcium chloride, and the solvent removed in vacuo. The residue was distilled in vacuo, and the fraction of b.p. >174° C./1.3 mbar was collected and redistilled. Material of b.p. >182° C./2.6 mbar in this second distillation was collected and redistilled to give 2-bromo-1-[1-(3,4-dichlorophenyl)cyclopentyl]ethanone as a pale yellow oil (11.8 g), b.p. 156°-162° C./0.4 mbar.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.ClC(OCC)=O.[NH2:34][CH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36]1>C(Cl)Cl>[CH:35]1([NH:34][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36]1
Reactant: NC1CCc2ccccc21
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)NC1CCc2ccccc21
Reaction time: 2 h

Procedure:
To a solution of 7.0 g linoleic acid in 250 ml methylenechloride cooled to -20° is added 2.5 g triethylamine, and then dropwise 2.7 g ethyl chloroformate. The reaction mixture is allowed to come to room temperature and then stirred 2 hours. To the reaction mixture is then added, dropwise, 3.4 g 1-aminoindan, and the reaction mixture then stirred for 16 hours. The reaction mixture is then extracted several times with 2 N hydrochloric acid, then with 2 N aqueous sodium hydroxide solution, washed well with saturated aqueous sodium chloride, dried over anh. sodium sulphate, filtered and the filtrate evaporated i.v. to dryness. The resulting residue is rapidly filtered over silica gel, with methylene chloride as solvent. The necessary fractions indicated to contain reaction product by thin layer chromatography of samples are pooled and solvent removed by evaporation under vacuum to give title product as a viscous oil, characterized by NMR (in CDCl3); triplet at 5.15 ppm (4 protons) and doublet at 6.4 ppm (1 proton).