Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11]2)=[CH:8][CH:9]=1
Reactant: CC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Product: CC(=O)N[C@@H]1CCN(c2ccc(N)cc2)C1
Yield: 95 %

Procedure:
N-[(3R)-1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide (Method 42; 4.5 g, 18 mmol) hydrogenated over 10% palladium/carbon at room temperature and 1 atmosphere pressure in absolute alcohol (200 ml). After filtration of the catalyst and evaporation at reduced pressure gave N-[(3R)-1-(4-aminophenyl)pyrrolidin-3-yl]acetamide as a red oil (3.75 g, 95%). NMR (CDCl3): 1.97 (s, 3H), 1.89-2.03 (m, 1H), 2.22-2.34 (m, 1H), 2.54 (s, 2H), 3.06-3.27 (m, 2H), 3.34-3.48 (m, 2H), 4.52-4.68 (m, 1H), 5.79 (brs, 1H), 6.48 (d, 2H), 6.69 (d, 2H); m/z 220. Treatment with 4M hydrogen chloride in 1,4-dioxane gave the title compound (4.21 g, 96%). LCMS: m/z 220.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](O)=[O:11])[CH:6]=[CH:7][CH:8]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:47][NH:48][O:49][CH3:50]>CN(C=O)C.C(OCC)(=O)C>[CH3:50][O:49][N:48]([CH3:47])[C:10](=[O:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=1
Reactant: CNOC
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
A solution of 3-(trifluoromethyl)phenylacetic acid (1.00 g, TCI) in DMF (15 ml) was added with WSC HCl (1.28 g, KOKUSAN), HOBT (794 mg, KOKUSAN), and DIEA (1.02 ml, ALD), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added with a solution of N,O-dimethylhydroxylamine hydrochloride (956 mg, WAKO) in DMF (5 ml) added with DIEA (1.74 ml) and stirred for 20 minutes at room temperature beforehand, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added with ethyl acetate (150 ml), successively washed with 1 N aqueous hydrochloric acid, purified water, saturated aqueous sodium hydrogencarbonate, and saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Intermediate pa-01, 893 mg).
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([N:8]=[C:9]([CH3:19])[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[C:4]=1[CH2:20][CH3:21].[CH3:22][N:23]([CH3:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C(O)(=O)C>[Cl-:1].[CH3:22][N:23]([CH3:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[N:2][N:3]2[CH:7]=[CH:6][N+:5]([N:8]=[C:9]([CH3:19])[C:10]3[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=3)=[C:4]2[CH2:20][CH3:21])=[CH:26][CH:25]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCc1n(N=C(C)c2ccc([N+](=O)[O-])cc2)cc[n+]1N
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=C(C)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 1.15 g (3.7 mmol) of 1-amino-2-ethyl-3-[(α-methyl-p-nitrobenzylidene)amino]-imidazolium chloride and 0.55 g (3.7 mmol) of p-dimethylaminobenzaldehyde in 25 ml of glacial acetic acid is stirred for 18 hours. The product is crystallized out by the addition of ether. The product is recrystallized from ethanol/ether. There is obtained 3-[[p-(dimethylamino)-benzylidene]amino]-2-ethyl-1-[(α-methyl-p-nitrobenzylidene)amino]-imidazolium chloride of melting point 233°.
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[NH:58]1[CH2:63][CH2:62][CH:61]([NH:64][C:65]2[CH:66]=[C:67]([CH:70]=[CH:71][CH:72]=2)[C:68]#[N:69])[CH2:60][CH2:59]1>CN(C)C=O.ClCCl.O1CCCC1>[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][C:19]([N:58]3[CH2:59][CH2:60][CH:61]([NH:64][C:65]4[CH:66]=[C:67]([CH:70]=[CH:71][CH:72]=4)[C:68]#[N:69])[CH2:62][CH2:63]3)=[O:20])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: N#Cc1cccc(NC2CCNCC2)c1
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(NC2CCN(C(=O)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)c1
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (120 mg; 0.37 mmol, prepared in accordance with Example 3), diisopropylethyl amine (150 μL; 0.85 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (129 mg; 0.34 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (2.5 mL) and the resulting solution is stirred for 5 minutes. A solution 3-(piperidin-4-ylamino)-benzonitrile hydrochloride (80 mg; 0.34 mmol, prepared in accordance with Example 6) in dimethylformamide (850 μL) is added and the reaction is then stirred for 60 minutes at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (67 mg; 0.14 mmol). The structure was confirmed using Protocol I-B. Calculated mass=500; observed mass=500; HPLC retention time=4.40 min.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:5]=1[CH2:6][O:7][CH2:8][CH2:9][OH:10].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:10][CH2:9][CH2:8][O:7][CH2:6][C:5]1[C:4]([Cl:3])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:15]
Reactant: OCCOCc1c(Cl)cccc1Cl
Reactant: BrCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1cccc(Cl)c1COCCOCCCCCCBr
Yield: 61.2 %

Procedure:
50% aq NaOH (1.89 L), 2-(2,6-dichlorobenzyloxy)ethanol (473.2 g), 1,6-dibromohexane (2.44 kg, 5 eq) and tetrabutylammonium bromide (34.1 g, 5 mol %) in toluene (1.89 L) was heated to 55-60° C. for 8-20 h. On cooling water (558 mL) and toluene (558 mL) were added. The aqueous phase was separated and diluted with water (1 L) then back extracted with toluene (1.1 L). The combined toluene extracts were washed twice with water (2.2 L), then evaporated to dryness on a rotary evaporator. The excess 1,6-dibromohexane was removed using a wiped film evaporator, and the resulting crude product chromatographed on silica (5 kg Biotage), eluting with 5% ethyl acetate in petrol 60/80, to give the title compound (503.2 g)−LC RT=7.0 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]([CH3:32])[NH:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:22]([C:21]5[C:16]([O:15][CH3:14])=[N:17][CH:18]=[CH:19][CH:20]=5)[CH:23]=4)[CH:28]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ncccc1-c1ccc2c(c1)CCNC2C
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: COc1ncccc1-c1ccc2c(c1)CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:43]=[CH:42][C:38]2[N:39]=[CH:40][S:41][C:37]=2[CH:36]=1.CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:35]2[CH:43]=[CH:42][C:38]3[N:39]=[CH:40][S:41][C:37]=3[CH:36]=2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2ncsc2c1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1cccc(-c2ccc3ncsc3c2)c1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (74 mg, 0.16 mmol), 6-bromo-benzothiazole (34.9 mg, 0.16 mmol), and Pd[P(Ph)3]4 (12.1 mg, 6.4 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 5.6 mg. MS: 458.1 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 1.18-1.25 (m, 2H), 1.76-2.00 (m, 3H), 2.10-2.34 (m, 1H), 4.28-4.40 (m, 1H), 4.87-5.10 (m, 2H), 7.00-7.56 (m, 7H), 7.68-7.66 (m, 1H), 7.97-8.15 (m, 2H), 8.33-8.39 (m, 1H), 9.35-9.39 (s, 1H), 10.09-10.16 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-]>CCOCC.[Cu]>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2([CH3:9])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)=COc1ccc(Cl)cc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu]
Solvent: CCOCC
Product: CCOC(=O)C1C(Oc2ccc(Cl)cc2)C1(C)C

Procedure:
A mixture of 3-(4-chlorophenoxy)-2-methyl-2-propene (4.5 g, 0.032 mol) and 0.158 g of copper powder is heated at 110° for 30 min; then 2.78 g ethyl diazoacetate (0.025 mol) is added dropwise, keeping the temperature at 110°. After the addition is complete (approximately 30 min), the mixture is stirred at 110° until nitrogen evolution is complete. The mixture is cooled, diluted with ether, filtered and concentrated. Distillation of the residue yields ethyl 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[CH3:18][C:19]1([CH3:27])[O:26][C:24](=[O:25])[CH2:23][C:21](=[O:22])[O:20]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>CCO>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][CH:23]2[C:24](=[O:25])[O:26][C:19]([CH3:27])([CH3:18])[O:20][C:21]2=[O:22])=[CH:12][CH:11]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc(F)cc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CC1(C)OC(=O)C(Cc2ccc(F)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Proline (5.748 g, 49.42 mmol) was added to a solution of 4-fluorobenzaldehyde (24.99 g, 197.3 mmol) and Meldrum's acid (29.01 g, 197.3 mmol) in EtOH (900 mL). The mixture was stirred at room temperature for 1.5 hours, then diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (50.99 g, 197.3 mmol) was added along with an additional 100 mL of EtOH. The mixture was stirred overnight and EtOH was removed under reduced pressure. The residue was triturated with i-PrOH and filtered to provide the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[S:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[OH:22].C[O:24][C:25](=[O:28])[CH2:26]Br.[OH-].[Na+].Cl>CN(C=O)C.O.C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[S:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[O:22][CH2:26][C:25]([OH:28])=[O:24]
Reactant: COC(=O)CBr
Reactant: CS(=O)(=O)c1ccc(Sc2cc(F)ccc2O)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Sc2cc(F)ccc2OCC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% disp. oil, 0.024 g) was added to the product from step (iv) (0.20 g) in dry DMF (10 ml) and stirred at RT for 30 min before adding methyl-bromoacetate (0.060 ml). The solution was stirred at RT for 2 h, diluted with water and extracted with diethylether. The organics were dried and evaporated under reduced pressure to give an oil. The oil was dissolved in THF (20 ml) and water (10 ml) then sodium hydroxide (0.037 g) was added and stirred at RT overnight. The mixture was acidified with 2M HCl, extracted with ethyl acetate, the organics dried and evaporated under reduced pressure. The residue was purified by reverse phase HPLC. Yield 0.045 g
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH:50]([O:52][C:53](=[O:60])[N:54]([CH2:58][CH3:59])[CH:55]([CH3:57])[CH3:56])[CH3:51]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH:50]([O:52][C:53](=[O:60])[N:54]([CH2:58][CH3:59])[CH:55]([CH3:56])[CH3:57])[CH3:51])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(=O)OC(C)Cl)C(C)C
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)OC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1)C(C)C
Yield: 54.3 %

Procedure:
To a solution of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 150 mg, 0.243 mmol) in dimethylformamide (6 mL) was added cesium carbonate (243 mg, 0.746 mmol). After stirring for a few minutes, a solution of the above freshly made ethyl-isopropyl-carbamic acid 1-chloro-ethyl ester (190 mg, 0.491 mmol) in dry dimethylformamide (1 mL) was added and the reaction mixture was allowed to stir at room temperature overnight. This reaction mixture was diluted with ethyl acetate and washed with water, brine and concentrated to dryness. The crude material was purified by chromatography (hexane/ethyl acetate, 90/10 to 10/90) to give 1-(ethyl(isopropyl)-carbamoyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid (102 mg, 54% yield). LCMS (ES+) m/z calcd. for C39H45Cl2F2N4O6 [(M+H)−]: 773, found: 773.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:16])[NH:11]2.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>>[N:17]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C:10](=[O:16])[NH:11]3)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: O=C1CCc2c(cccc2OCCCCl)N1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CCc2c(cccc2OCCCN2CCNCC2)N1
Yield: 49.7 %

Procedure:
(a)-1 3.0 grams of 5-(3-chloropropoxy)-3,4-dihydrocarbostyril and 10 g of piperazine are mixed with 20 ml of hexamethylphosphoryl triamide and heated at 80°-90° C. for 5 hours. The reaction mixture is distilled under a reduced pressure to remove hexamethylphosphoryl triamide and unreacted piperazine. To the residue thus obtained are added 30 ml of 5%-NaHCO3 aqueous solution, followed by extraction with chloroform. The chloroform layer is washed with water and chloroform is removed by distillation. The residue thus obtained is purified by silica-gel chromatography to obtain 1.8 g of 5-(3-piperazinylpropoxy)-3,4-dihydrocarbostyril having a melting point of 192°-195° C.
Reaction SMILES: FC1C(C(O)=O)=C([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)C(C)=CC=1.[F:17][C:18]1[C:19]([CH3:28])=[CH:20][C:21](I)=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24]>>[F:17][C:18]1[C:19]([CH3:28])=[CH:20][C:21]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24]
Reactant: Cc1ccc(F)c(C(=O)O)c1-n1nccn1
Reactant: Cc1cc(I)c(C(=O)O)cc1F
Product: Cc1cc(-n2nccn2)c(C(=O)O)cc1F

Procedure:
The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A352 using 5-fluoro-2-iodo-4-methylbenzoic acid. MS (ESI) 222 (M+H).
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH:7]=[C:6]([O:8][CH3:9])[S:5][C:4]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:30]([O:32][C:33](=[O:44])[CH:34]=[C:35]([CH3:43])[CH:36]=[CH:37][CH:38]=[C:39]([CH:41]=O)[CH3:40])[CH3:31].C1OCCC1>C1(C)C=CC=CC=1>[CH2:30]([O:32][C:33](=[O:44])[CH:34]=[C:35]([CH3:43])/[CH:36]=[CH:37]/[CH:38]=[C:39]([CH3:41])[CH:40]=[CH:10][C:4]1[S:5][C:6]([O:8][CH3:9])=[CH:7][C:3]=1[CH3:2])[CH3:31]
Reactant: COc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)s1
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)/C=C/C=C(C)C=Cc1sc(OC)cc1C

Procedure:
A suspension of 5.9 g. (13.5 mmol) of (3-methyl-5-methoxy-2-thenyl)triphenyl phosphonium chloride and 2.81 g. (13.5 mmol) of ethyl-7-formyl-3-mehtyl-2,4,6-octatrienoate in 70 ml. of butylene oxide and 200 ml. of toluene was heated to 100° C. for 14 hrs. The resulting clear solution was cooled, poured into 500 ml. of a methanol/water mixture (6:4) and extracted with hexane. The combined hexane extracts were washed with methanol/water (6:4), dried and evaporated. The resulting crude, oily material was purified by chromatography (silica gel, hexane/ether, ratio 7:3) to yield after recrystallization from hexane all trans-3,7-dimethyl-9-(3-methyl-5-methoxy-2-thienyl)-2,4,6,8-nonatetraenoic acid ethyl ester, m.p. 66°-72° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Cl[C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([S:30]([CH3:32])=[O:31])[N:29]=1)[C:23]([O:25][CH3:26])=[O:24]>>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:20]2[CH:21]=[C:22]([CH:27]=[C:28]([S:30]([CH3:32])=[O:31])[N:29]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:15][CH2:14]1)=[O:11]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: COC(=O)c1cc(Cl)nc(S(C)=O)c1
Agent: Cl
Product: COC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(S(C)=O)c1

Procedure:
The title compound was prepared in a manner analogous to Example 6 starting from 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1) and methyl 2-chloro-6-(methylsulfinyl)isonicotinate (Intermediate 84).
Reaction SMILES: Br[CH:2]([C:5]1([O:20][CH2:21][CH3:22])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)[CH2:3][OH:4].C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>[CH2:21]([O:20][C:5]1([CH2:2][CH2:3][OH:4])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)[CH3:22]
Reactant: CCOC1(C(Br)CO)c2ccccc2COc2ccccc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC1(CCO)c2ccccc2COc2ccccc21
Temperature: 25 °C
Yield: 55.4 %

Procedure:
Dissolved 2-bromo-2-[6,11-dihydro-11-ethoxy-dibenz[b,e]oxepin-11-yl]-ethanol (14.34 g, 0.0395 mol) in 150 mL of dry toluene. Added tri-n-butyl tin hydride (17.24 g, 15.9 mL, 0.0592 mol) and AIBN (0.324 g, 0.00197 mol). Refluxed under a nitrogen atmosphere for 18 hours. Cooled to room temperature, and evaporated. Dissolved residue in 300 mL of acetonitrile, and washed with hexane to remove tin by-products. Dried acetonitrile solution with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 1:4 ethyl acetate:hexane then 1:3 ethyl acetate:hexane. Combined appropriate fractions, and evaporated to give 6.22 g (55% yield) of 2-[6,11-dihydro-11-ethoxydibenz[b,e]oxepin-11-yl]-ethanol as a colorless oil.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=1.C(N(CC)CC)C.CN1C(=O)CCC1>O>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: c1ccc(Cc2nnc(N3CCNCC3)c3ccccc23)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Temperature: 180 °C
Yield: 70 %

Procedure:
1-Benzyl-4-piperazin-1-yl-phthalazine (500 mg, 1.64 mmol) and 2-chloro-5-nitropyridine are combined in a 10 mL microwave vial. Triethylamine (2.96 mL, 2.14 mmol) and NMP (4.8 mL) are added. The vial is sealed and heated to 180° C. for 15 min. The crude reaction mixture is poured into water and the resulting precipitate is isolated by filtration to afford the title compound (500 mg, 70% yield).
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.C[O:18][C:19]1[CH2:23][CH2:22][C:21](=O)[CH:20]=1>O1CCCC1>[C:2]1([C:21]2[CH2:22][CH2:23][C:19](=[O:18])[CH:20]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COC1=CC(=O)CC1
Reactant: Ic1cccc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1C=C(c2cccc3ccccc23)CC1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
To a stirred solution of 1-iodonapthalene (10.00 g, 39.36 mmol) in tetrahydrofuran (300 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes; 17.49 mL, 43.73 mmol, 1.1 eq.) so that the reaction temperature remained ≦−78° C. The reaction mixture was stirred for 15 minutes. To the reaction mixture was added a solution of 3-methoxy-2-cyclopenten-1-one (5.10 g, 45.48 mmol, 1.16 eq.) in tetrahydrofuran (50 mL) so that the reaction temperature remained ≦−78° C. The reaction mixture was warmed to −20° C. over a 2 h period and the reaction mixture was quenched with a solution of 1N HCl and concentrated in vacuo to remove the organics. A solution of 1N HCl was added and the reaction mixture was stirred for a further 0.5 h and extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (100 mL) followed by brine (100 mL), dried over magnesium sulphate and concentrated in vacuo to afford a yellow oil. The crude oil was purified by flash chromatography (SiO2, ethyl acetate:petroleum ether 40-60; 20%:80%) to afford the desired compound as an off-white solid (4.01 g, 49%). 1H NMR (400 MHz, CDCl3) δ ppm 2.68 (2H, dt, J 2, 4.8 Hz, CH2), 3.16 (2H, td, J 2.4, 4.8 Hz, CH2), 6.51 (1H, t, J 1.6 Hz, CH), 7.54-7.60 (4H, m, ArH), 7.93-8.01 (2H, m, ArH), 8.10-8.18 (1H, m, ArH).