Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([NH2:22])[CH:19]=[N:18]2)=[CH:13][CH:12]=1.[OH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[OH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:22][C:20]2[CH:19]=[N:18][N:17]([C:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:3]4[CH2:4][CH2:5][CH2:6][C@H:2]4[CH3:1])=[CH:12][CH:13]=3)[CH:21]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(N)cn2)cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(NC(=O)c3ccc(O)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A suspension of 1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-ylamine obtained in Example 29-(1) (0.191 g), 4-hydroxybenzoic acid (0.097 g), 1-hydroxybenzotriazole monohydrate (0.107 g) and 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (0.18 g) in chloroform (6.4 mL) was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH-type silica gel column chromatography (eluting solvent: chloroform→chloroform:methanol=10:1) to give the titled compound (0.137 g) as a colorless amorphous substance.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[N:13]1([C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=O)[CH:17]=[CH:16][CH:15]=[N:14]1.[CH2:27]([NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:28]1[CH:36]=[CH:35][C:34]2[O:33][CH2:32][O:31][C:30]=2[CH:29]=1>O1CCCC1>[O:33]1[C:34]2[CH:35]=[CH:36][C:28]([CH2:27][N:37]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:20](=[O:22])[C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[N:13]3[CH:17]=[CH:16][CH:15]=[N:14]3)=[CH:29][C:30]=2[O:31][CH2:32]1
Reactant: O=C(O)c1ccccc1-n1cccn1
Reactant: c1ccc(CNCc2ccc3c(c2)OCO3)cc1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: O=C(c1ccccc1-n1cccn1)N(Cc1ccccc1)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
1.1 equiv of carbonyl diimidazole is added to a solution of benzoic acid 178 (200 mg) in tetrahydrofuran (5 mL); the reaction is stirred at room temperature for 3 h. After this time N-piperonyl-N-benzylamine (0.25 g) is added in one portion. After 30 min, the reaction is filtered, diluted with ether and washed with water. The organic layer is dried (Na2SO4) and purified over column chromatography to provide the desired product (390 mg). The proton NMR displays a typically doubled pattern. 1H (CDCl3) 3.83 and 4.32 (two doublets, J=16 Hz, 1H), 3.91 (two doublets, J=8 Hz, 1H), 4.18 two doublets (J=6 Hz, 1H), 5.0 and 5.1 (two doublets, J=14 Hz, 1H), 5.93 and 5.98 (s and doublet, J=2 Hz, 2H, OCH2O), 6.35-6.40 (m, 2H), 6.51 (d, J=4 Hz, 0.5H), 6.4 (m, 1.5H), 7.0-7.88 m, 15H). LC-MS 412.3.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[OH:12][C:13](C(F)(F)F)=O.OC(C(F)(F)F)=O.[OH:26]/[N:27]=[C:28](\[NH2:57])/[C:29]([CH3:56])([NH:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([NH:44][C:45]3[N:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[CH:47][N:46]=3)[CH:41]=[C:40]([CH3:55])[CH:39]=2)=[CH:34][N:33]=1)[CH3:30].C1N=CN(C(N2C=NC=C2)=O)C=1>O1CCOCC1>[CH3:55][C:40]1[CH:39]=[C:38]([C:35]2[CH:36]=[CH:37][C:32]([NH:31][C:29]([C:28]3[NH:57][C:13](=[O:12])[O:26][N:27]=3)([CH3:30])[CH3:56])=[N:33][CH:34]=2)[CH:43]=[C:42]([NH:44][C:45]2[N:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[CH:47][N:46]=2)[CH:41]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(NC(C)(C)/C(N)=N/O)nc2)c1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(NC(C)(C)c3noc(=O)[nH]3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DBU (10.0 μL, 0.066 mmol) was added to a mixture of (1Z)—N′-hydroxy-2-methyl-2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}propanimidamide bis-TFA salt (14.0 mg, 0.025 mmol) and CDI (4.26 mg, 0.026 mmol) in dioxane (100 μL). The reaction was stirred at room temperature overnight. The reaction mixture was filtered, diluted with DMF (500 μL), and directly purified by reverse phase HPLC. The isolated material was repurified by silica gel chromatography (0-100% ethyl acetate in hexanes with 1% triethylamine and then 20% methanol in dichloromethane) to yield 3-(2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}propan-2-yl)-1,2,4-oxadiazol-5(4H)-one. MS APCI calc'd for C22H21F3N7O2 [M+H]+ 472. found 472. 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J=5.2 Hz, 1H), 8.34 (s, 1H), 7.79 (d, J=11.5 Hz, 2H), 7.41 (s, 1H), 7.31 (s, 1H), 7.05 (d, J=5.2 Hz, 2H), 6.64 (d, J=9.1 Hz, 1H), 2.43 (s, 3H), 1.80 (s, 6H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.[N+](=[CH2:19])=[N-]>CO>[OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:19])=[O:15])=[CH:3]1
Reactant: O=C(O)CCCCCCC1=CC(O)CC1=O
Reactant: C=[N+]=[N-]
Solvent: CO
Product: COC(=O)CCCCCCC1=CC(O)CC1=O

Procedure:
To 1.0 part of 3(RS)-hydroxy-5-oxocyclopent-1-eneheptanoic acid dissolved in methanol is added dropwise a 5% ethereal diazomethane solution until a slight excess of diazomethane is present. That excess is detected when the solution exhibits a persistent yellow color. The solution then is evaporated to dryness under a nitrogen atmosphere to yield methyl 3(RS)-hydroxy-5-oxocyclopent-1-eneheptanoate.
Reaction SMILES: C(NCC)C.[C:6]([O:10][C:11](=[O:41])[CH2:12][C@H:13]([NH:23]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:14]([N:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1)=[O:15])([CH3:9])([CH3:8])[CH3:7]>CN(C)C=O>[C:6]([O:10][C:11](=[O:41])[CH2:12][C@H:13]([NH2:23])[C:14]([N:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1)=[O:15])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCC(O)CC1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC(C)(C)OC(=O)C[C@H](N)C(=O)N1CCC(O)CC1
Reaction time: 1 h

Procedure:
Diethylamine (1.0 mmol) was added to (S)-3-(9H-fluoren-9-ylmethoxycarbonyl-amino)4-(4-hydroxy-piperidin-1-yl)4-oxo-butyric acid tert-butyl ester in dimethylformamide (5 ml) at 25° C. After 1 hour, the reaction mixture was concentrated, the residue suspended in 1:1 ether/dichloromethane, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with 1-50% ethanol in dichloromethane containing 0.5% ammonium hydroxide. Yield 217 mg, 80%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)C>O1CCCC1>[CH2:23]([NH:30][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)CCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: NCc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)c1cnc2c(OC)cccc2c1NCc1ccccc1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
In a flame-dried, three-necked round-bottomed reaction flask equipped with reflux condenser, magnetic stirring bar and rubber septum, there were placed 3.0 g (0.0093 mole) of 4-chloro-3-(3-ethoxycarbonylpropionyl)-8-methoxyquinoline (the product of Preparation C) dissolved in 30 mL of dry tetrahydrofuran. Stirring was commenced and to the resulting ethereal solution were then added with 2.0 g (0.0186 mole) of benzylamine (available from the Eastman Kodak Company of Rochester, N.Y.), which was added over a five-minute period at room temperature (ca. 20° C.). The well-stirred reaction mixture was then heated to 60° C. and thereafter kept at that temperature for a period of six hours. Upon completion of this step (as revealed by thin layer chromatography (TLC) analysis), the final reaction mixture was filtered to remove precipitated benzylamine hydrochloride and the filtrate was subsequently evaporated to near dryness while under reduced pressure to afford a solid material as the residue. Trituration of the latter material with diethyl ether then gave 880 mg (22%) of essentially pure 4-benzylamino-3-(3-ethoxycarbonylpropionyl)-8-methoxyquinoline as the free base compound: mass spectrum, m/e 392; NMR (CDCL3) consistent with product. The latter batch of material was next dissolved in dry benzene and thereafter treated with anhydrous hydrogen chloride gas to ultimately yield 320 mg (8%) of pure 4-benzylamino-3-(3-ethoxycarbonylpropionyl)-8-methoxyquinoline as the hydrochloride salt (in the form of a monohydrate), m.p. 201°- 202° C. after one recrystallization from methanol-diethyl ether. The pure product was further characterized by means of mass spectrum (MS) analysis, in addition to elemental analysis. Mass spectrum, m/e 392.
Reaction SMILES: [Cl:1][CH2:2][C:3](N(C)C)=[O:4].O=P(Cl)(Cl)Cl.[CH:13]1[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[CH:22]2)[CH2:18][CH2:17][CH2:16][N:15]3[CH:14]=1.[OH-].[Na+]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([C:13]1[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[CH:22]2)[CH2:18][CH2:17][CH2:16][N:15]3[CH:14]=1)=[O:4]
Reactant: c1cc2c3c(c1)ccn3CCC2
Reactant: CN(C)C(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(CCl)c1cn2c3c(cccc13)CCC2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of 2-chloro-N,N-dimethyl-acetamide (10 mL, 97.5 mmol) was added POCl3 (14 mL, 149.5 mmol). The clear mixture was stirred at room temperature for 20 min 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (10.20 g, 65.0 mmol, for preparation see WO06086486A1) was added. The mixture was stirred at 80° C. for two hours. The mixture was poured on to ice (200 mL) and dichloromethane (300 mL). Aqueous sodium hydroxide was added to adjust to pH>12. The dichloromethane layer was separated, washed with water (300 mL), dried over Na2SO4, filtered and evaporated to give a dark solid. The solid was dissolved into DCM and purified by silica gel column chromatography (eluent: 0% to 1% EtOAc in DCM). 2-Chloro-1-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-ethanone was obtained as an off-white solid (10.82 g, 71%) after tituration with EtOAc. M.p.=118-119° C.; 1H NMR (400 MHz, CDCl3) δ: 8.00 (d, J=8.0 Hz, 1H), 7.82 (s, 1H), 7.23 (m, 1H), 7.03 (d, J=7.2 Hz, 1H), 4.51 (s, 2H), 4.21 (t, J=6.0 Hz, 2H), 3.01 (t, J=6.0 Hz, 2H), 2.27 (m, 2H). LCMS: m/e 234.03 [M+H].
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([NH:10][NH2:11])=[O:9].[C:12](=S)=[S:13].Cl>CO>[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[O:9][C:12]([SH:13])=[N:11][N:10]=1
Reactant: NNC(=O)c1ccc[nH]1
Reactant: S=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Sc1nnc(-c2ccc[nH]2)o1
Reaction time: 0.5 h

Procedure:
Potassium hydroxide (4.78 g, 85.3 mmol) was solved in methanol (125 ml). 1H-pyrrole-2-carbohydrazide (9.7 g, 77.5 mmol) was added and the mixture was stirred for 30 minutes. Carbon disulfide (14.7 g, 193.8 mmol) was added to the mixture followed by stirring at 65° C. for 15 h. Another equivalent of carbon disulfide (5.90 g, 77.5 mmol) was added followed by stirring at 65° C. for 4 days. Aqueous hydrochloric acid (1 M) was added in excess quantity, the mixture was stirred and filtered and washed with aqueous hydrochloric acid. Yield 10 g (77%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:22]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)[CH3:12]
Reactant: CC(c1cc2cccnc2cc1F)c1nnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2nnc(C(C)c3cc4cccnc4cc3F)n2n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)-7-fluoroquinoline (100 mg, 0.305 mmol), PdCl2(PPh3)2 (21.4 mg, 0.031 mmol) and tributyl(1-ethoxyvinyl)stannane (220 mg, 0.61 mmol) in 5 mL of 1,4-dioxane was heated at 90° C. for 5 h under nitrogen. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in HOAc and 3 N HCl, and stirred at rt for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM, washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/MeOH gradient to afford the title compound as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.87 (d, 1H), 8.16 (d, 1H), 8.03 (d, 1H), 7.80 (d, 1H), 7.73 (d, 2H), 34 (dd, 1H), 5.39 (q, 1H), 2.62 (s, 3H), 2.09 (d, 3H). LCMS (method A): [MH]+=336, tR=4.95 min.
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[N:9]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[O:32])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:41]([O:45][C:46](=[O:49])[CH2:47]Br)([CH3:44])([CH3:43])[CH3:42].O>C(#N)C>[C:41]([O:45][C:46](=[O:49])[CH2:47][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[N:9]([C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]2=[O:32])=[CH:33][CH:34]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(4-hydroxybenzyl)-3-tritylthiazolidin-2,4-dione (20.0 g) in acetonitrile (200 ml) was added cesium carbonate (21.0 g), followed by bromoacetic acid t-butyl ester (7.4 ml) and the mixture was stirred at 25° C. for 3 hours. To the reaction mixture was added water and the organic layer was separated and concentrated in vacuo. The residue was extracted with toluene and the extract was washed with diluted hydrochloric acid and water and concentrated in vacuo to give the desired compound (24.9 g).
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:14])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCc1ccc(CCl)cc1
Yield: 97 %

Procedure:
In 50 ml of chloroform was dissolved 8.63 g (57.5 mmol) of 4-n-propylbenzyl alcohol synthesized in the step (ii), and 8.10 g (68.1 mmol) of thionyl chloride was added to the mixture. The mixture was subjected to reaction at a room temperature for 24 hours. After the completion of the reaction, the chloroform phase was washed successively with an aqueous solution of sodium hydrogencarbonate and water. Chloroform was removed from the chloroform phase to give 9.40 g (55.8 mmol) of 4-n-propylbenzylchloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[C:11]([F:17])[C:10]=1[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([Li])CCC.CCCCCC.[C:30](=[O:32])=[O:31].Cl>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([F:18])=[C:11]([F:17])[C:12]([C:30]([OH:32])=[O:31])=[C:13]([F:16])[C:14]=1[F:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=C=O
Reactant: CCCCCCCOc1c(F)c(F)cc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCOc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
31.8 g of the compound (6) dissolved in 250 mL of THF were cooled at −78° C. in an argon atmosphere; thereto were then dripped 93 mL of a 1.6 M/L n-butyllithium/hexane solution, with stirring for 2 hours at the same temperature. After addition of a suitable amount of crushed dry ice, the temperature was raised to room temperature, followed by stirring overnight. 200 mL of 3N hydrochloric acid were then added under ice cooling, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. After evaporating the solvent, the organic layer was recrystallized from hexane to yield 12.9 g (41 mmol) of 4-heptyloxy-2,3,5,6-tetrafluorobenzoic acid (7).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[CH:20](Br)([CH3:22])[CH3:21].O>CN(C=O)C>[CH:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1)([CH3:22])[CH3:21]
Reactant: O=C1CCCCc2ccc(O)cc21
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc2c(c1)C(=O)CCCC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a suspension of 2-hydroxy-6,7,8,9-Tetrahydro-5H-benzocyclohepten-9-one (9.69 g, 56.3 mmol) and potassium carbonate (23.3 g, 0.17 mol) in DMF (60 ml) was added dropwise, under ice-cooling, isopropyl bromide (34.6 g, 0.28 mol). The reaction mixture was stirred for one hour at 100° C., which was poured into water, followed by extraction of the organic substance with ethyl acetate. The extract solution was washed with brine and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=9:1) to give the above-titled compound (11.4 g, yield 93%, oil).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH2:10]([Mg]Br)[CH3:11].B(F)(F)F.O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2([NH2:9])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(C#N)nc1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(C2(N)CC2)nc1

Procedure:
To a solution of 5-methylpyrimidine-2-carbonitrile (200 mg, 1.7 mmol, 1 eq) in dry THF under an argon atmosphere was added titanium isopropoxide (0.58 ml, 2.0 mmol, 1.2 eq) slowly at ambient temperature and the reaction mixture was stirred for 15 mins Ethyl magnesium bromide (1M solution) in THF (4 ml, 4.0 mmol, 2.4 eq) was added via syringe slowly at ambient temperature. Then the reaction mixture was stirred for an hour. BF3.EtO (0.36 ml, 2.6 mmol, 1.5 eq) was added slowly through syringe to the mixture at 0° C. The mixture was allowed to attain ambient temperature and stirred for another one hour. 10 ml of water was added to the reaction mixture which was then filtered through Celite and the bed washed with water and ethyl acetate. The filtrate was basified with 10% NaOH solution (pH=9) then extracted with DCM. The organic was washed with brine solution, dried over sodium sulphate and concentrated to give the crude product which was taken for coupling reaction without further purification. Yield: 125 mg (crude).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][NH:5]1.C(N(CC)CC)C.[C:18]([C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)#[N:19]>C(Cl)Cl>[C:18]([C:20]1[CH:21]=[C:22]([S:26]([N:5]2[CH2:6][C@@H:7]([OH:9])[CH2:8][C@H:4]2[C:3]([O:2][CH3:1])=[O:10])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)#[N:19]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](O)CN1S(=O)(=O)c1cccc(C#N)c1
Reaction time: 1 h

Procedure:
To a solution of cis-4-hydroxy-L-proline methyl ester (10.0 g, 68.8 mmol), triethylamine (13.9 g, 138 mmol), and CH2Cl2 (200 mL) was added 3-cyanobenzene-1-sulfonyl chloride (13.9 g, 68.8 mmol). After 1 h, the reaction was partitioned between saturated aqueous NaHCO3 (75 mL) and CH2Cl2 (100 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×75 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified on silica gel (1:99→30:70 ethyl acetate-hexanes) to afford the title compound as a colorless crystalline solid: 1H NMR (500 MHz, CDCl3) δ 8.19-8.18 (m, 1H), 8.13-8.11 (m, 1H), 7.89-7.85 (m, 1H), 7.69-7.65 (t, 1H), 4.52-4.50 (m, 1H), 4.44-4.43 (m, 1H), 3.67 (s, 3H), 3.52 (dd, 1H), 3.47-3.41 (m, 1H), 3.1 (d, 1H), 2.33-2.27 (m, 1H), 2.20-2.17 (m, 1H); LRMS (ESI) m/z 311 (311 calcd for C13H14N2O5S, M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: Fc1cccc2cc[nH]c12
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: Fc1cccc2c(C3=CCNCC3)c[nH]c12
Yield: 65.6 %

Procedure:
Beginning with 2.0 gm (14.8 mMol) 7-fluoro-1H-indole and 4.6 gm (30.0 mMol) 4-piperidone hydrochloride monohydrate, 2.1 gm (66%) of the title compound were recovered as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH:16]([NH:20][S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH:17]3[CH2:19][CH2:18]3)[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[H-].[Na+].I[CH2:29][CH3:30]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH:16]([N:20]([CH2:29][CH3:30])[S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH:17]3[CH2:19][CH2:18]3)[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCI
Reactant: CCS(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1)S(=O)(=O)CC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 40 mL scintillation vial was charged with ethanesulfonic acid {[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-cyclopropyl-methyl}-amide (0.075 g, 0.200 mmol) and DMF (3 mL). The reaction mixture was cooled to 0° C. and sodium hydride (0.012 g, 0.299 mmol) was added. The reaction was left to stir at room temperature for 20 min followed by the addition of iodoethane (0.050 g, 0.319 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with water (0.5 mL) and filtered. The filtrate was dissolved in DMF (3 mL) and purified using Xbridge C18 eluting with a 10 to 100% ACN-water to afford pure product ethanesulfonic acid {[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-cyclopropyl-methyl}-ethyl-amide as a white color solid. HRMS: (ESI) m/z 404.1190 [(M+H)+ Calcd for C20H22ClN3O2S 404.1199]. 1H NMR (400 MHz, MeOD) δ ppm 0.52-0.68 (m, 1H), 0.71-0.82 (m, 1H), 0.91-1.05 (m, 2H), 1.22 (t, J=7.1 Hz, 3H), 1.43 (t, J=7.5 Hz, 3H), 1.60-1.88 (m, 1H), 3.28 (q, J=7.3 Hz, 2H), 3.39-3.51 (m, 1H), 3.55-3.66 (m, 1H), 4.32 (d, J=10.6 Hz, 1H), 7.93 (dd, J=8.1, 1.8 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 8.15 (d, J=1.5 Hz, 1H), 8.87 (s, 1H), 9.04 (d, J=1.8 Hz, 1H), 9.14 (d, J=1.8 Hz, 1H).