Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](C([Sn])=C(CCCC)CCCC)[CH2:2]CC.Br[C:17]1[CH:22]=[C:21]([O:23][CH:24]([F:26])[F:25])[CH:20]=[C:19]([Br:27])[CH:18]=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.[OH-].[Na+]>C1(C)C=CC=CC=1.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>[Br:27][C:19]1[CH:18]=[C:17]([CH:1]=[CH2:2])[CH:22]=[C:21]([O:23][CH:24]([F:26])[F:25])[CH:20]=1
Reactant: FC(F)Oc1cc(Br)cc(Br)c1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=Cc1cc(Br)cc(OC(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Tri(butyl)vinyltin (10.5 g, 33.1 mmol) was added dropwise to a solution of 1,3-dibromo-5-difluoromethoxybenzene (9.1 g, 30.1 mmol; see step (i) above), tetrakis(triphenylphosphine)palladium(0) (700 mg, 0.60 mmol), and 2,6-di-tert-butyl-4-methylphenol (spatula tip) in toluene (125 mL) under nitrogen. The mixture was stirred at 50° C. overnight. The mixture was cooled to 0° C. and 1N NaOH (70 mL) was added. After 1 h, the mixture was extracted with CH2Cl2 (3×300 mL) then, the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with hexanes afforded the sub-title compound (5.1 g, 68%) as a colourless oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:11][C:10]2[CH:12]=[C:13]([Br:16])[CH:14]=[CH:15][C:9]=2[C:8]=1[CH3:17].[CH2:18]=[O:19].O>CCCCCC.CCOCC>[Br:16][C:13]1[CH:14]=[CH:15][C:9]2[C:8]([CH3:17])=[C:7]([CH2:18][OH:19])[S:11][C:10]=2[CH:12]=1
Reactant: Cc1c(Br)sc2cc(Br)ccc12
Reactant: C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1c(CO)sc2cc(Br)ccc12
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
A solution of n-butyl-lithium in hexane (13.2 ml of 1.55 M solution) was added dropwise to a stirred solution of 2.6-dibromo-3-methylbenzo[b]thiophene (6.60 g) in dry ether (150 ml) at 0° under dry nitrogen and the mixture was stirred at 0° for 30 minutes. Paraformaldehyde (0.71 g) was then added portionwise and the mixture was stirred at 0° for 3 hours. Water was added and the layers were separated. The ether layer was washed with water, dried (Na2SO4) and evaporated to give an oil which was chromatographed on silica gel. Elution with chloroform first gave some impurity followed by pure product. Evaporation of the product-containing fractions gave a solid which was crystallised from ethyl acetate/petrol (b.p. 60°-80°) to give 6-bromo-2-hydroxymethyl-3-methylbenzo[b]thiophene (3.20 g), m.p. 95°-96°.
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=1.C[Si](C#N)(C)C>C(#N)C>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:1]#[N:3])[CH:11]=1
Reactant: CCN(CC)CC
Reactant: COc1cc[n+]([O-])cc1
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: COc1ccnc(C#N)c1
Reaction time: 0.33 h

Procedure:
In an argon atmosphere, triethylamine (17.8 mL) was added to 4-methoxypyridine-N-oxide (8.0 g) in acetonitrile (160 mL) at room temperature. Trimethylsilyl cyanide (24.1 mL) was added dropwise to the mixture, followed by stirring for 20 minutes. Subsequently, the mixture was stirred at 95° C. for 14 hours, and then cooled in air. The solvent was evaporated under reduced pressure. The residue was partitioned between saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate. The organic layer was dried over sodium hydrogensulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound as a solid substance (1.57 g, 18%).
Reaction SMILES: C([O:4][C@H:5]([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17](COCC)[C:16]([NH:25][CH3:26])=[N:15][C:14]=2[N:13]([CH3:27])[C:11]1=[O:12])(=O)C>CO.Cl>[OH:4][C@H:5]([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([NH:25][CH3:26])=[N:15][C:14]=2[N:13]([CH3:27])[C:11]1=[O:12]
Reactant: CCOCn1c(NC)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Agent: Cl
Solvent: CO
Product: CNc1nc2c([nH]1)c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Yield: 41.8 %

Procedure:
A solution of (R)-1-(5-acetoxyhexyl)-7-ethoxymethyl-3-methyl-8-methylaminoxanthine (0.32 g) in methanol (10 ml) was heated in presence of concentrated hydrochloric acid (2 drops) for 12 hours to 70° C. After evaporation of the solvent under reduced pressure, the residue was dissolved in 20% methanol-ethyl acetate (50 ml). The solution was washed with saturated sodium bicarbonate solution (20 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% methanol-ethyl acetate to provide (R)-1-(5-hydroxyhexyl)-3-methyl-8-methylaminoxanthine (0.100 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1cc(I)ccc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a stirred solution of 2-bromo-5-iodobenzoic acid (25.0 g, 76.48 mmol) in dichloromethane (200 mL) was added oxalylchloride (10.3 mL, 114.74 mmol) at 0° C. followed by DMF (0.9 mL). After complete addition, the reaction mixture was stirred at room temperature for 3 h. Volatiles were evaporated under reduced pressure to furnish 2-bromo-5-iodo-benzoyl chloride (26.4 g). The crude product was used for the next step immediately.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([N+:12]([O-])=O)[C:3]=1[NH:4][CH3:5]>C(O)(=O)C.[Fe]>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([NH2:12])[C:3]=1[NH:4][CH3:5]
Reactant: CNc1c([N+](=O)[O-])ccc(OC)c1F
Agent: [Fe]
Solvent: CC(=O)O
Product: CNc1c(N)ccc(OC)c1F
Reaction time: 22 h

Procedure:
A solution of 2-fluoro-3-methoxy-N-methyl-6-nitroaniline (7-2, 1.04 g, 5.20 mmol) in Acetic acid (25 ml) was charged with Iron (powder). The resulting mixture was stirred at 23 deg C. for 22 h. The reduced material concentrated in vacuo, and the residual oil was taken up in Methylene Chloride and filtered through Celite. The filtrate was again concentrated in vacuo, leaving the title compound, 3-fluoro-4-methoxy-N2-methylbenzene-1,2-diamine (7-3), as a maroon oil with >80% purity. LRMS m/z: Calc'd for C8H11FN2O (M+H) 171.2, found 170.9.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-benzyloxycarbonyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (3.06 g, 10.0 mmol) in dry DMF (30 ml) was added dropwise to a slurry of sodium hydride (60% dispersion in oil/480 mg, 12.0 mmol) in dry DMF (20 ml) under nitrogen at room temperature. The reaction mixture was stirred for one hour at room temperature to which was added dropwise tert-butyl bromoacetate (1.48 ml, 10.0 mmol). The reaction was stirred for a further two hours, diluted with ethyl acetate (100 ml), washed with brine (2×100 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with ethyl acetate-hexane (2:5) as eluant. (3.28 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:31]=[CH:32][C:33]=2[CH3:34])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:31]=[CH:32][C:33]=3[CH3:34])[CH2:24][CH2:23]2)=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCCC1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(F)cc3Cl)CCCCC2)CC1

Procedure:
Example 134 was prepared from 1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.55 (dd, 1H, J=8.9, 6.3 Hz), 7.32 (s, 1H), 7.23–7.18 (m, 2H), 7.06 (dd, 1H, J=8.5, 3.0 Hz), 7.01–6.92 (m, 2H), 5.99–5.93 (m, 1H), 3.24 (q, 2H, J=5.9 Hz), 2.85–2.79 (m, 3H), 2.59–2.50 (m, 1H), 2.44 (septet, 1H, J=7.0 Hz), 2.41–2.37 (br, 1H), 2.26 (t, 2H, J=5.7 Hz), 2.19 (s, 3H), 2.07–2.01 (m, 2H), 1.81–1.69 (m, 4H), 1.61–1.37 (m, 10H), 1.17 (d, 6H, J=7.0 Hz); ESMS m/e: 556.1 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:4]=1.Br[C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[F:23][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:25]3[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:4]=1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(OCC)c3)nc12
Product: CCOc1cccc(-c2cc(C(F)F)n3ncc(C#Cc4cccc(S(N)(=O)=O)c4)c3n2)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.19) (313 g, 1.0 mmol) and commercially available 3-bromobenzene-sulfonamide (307 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow foam (50 mg, 11%). MS (ISP) 469.3 [(M+H)+]; mp 167-168° C.
Reaction SMILES: I[C:2]1[C:6]([C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])=[CH:5][N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(N(C(C)C)C(C)C)C.CCOC(C)=O>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:6]([C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])=[CH:5][N:4]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:3]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1ccc(Cn2cc(C(=O)N(C)OC)c(I)n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2cc(C(=O)N(C)OC)c(-c3ccc(F)cc3)n2)cc1
Temperature: 180 °C
Yield: 90.8 %

Procedure:
According to Scheme 11 Step 1: A solution of 3-iodo-N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carboxamide (2.49 mmol, 1.00 g), 4-fluorophenylboronic acid (2.99 mmol, 419 mg), Pd(dppf)Cl2 (0.25 mmol, 204 mg) and N-ethyl-N-isopropylpropan-2-amine (4.99 mmol, 850 μL) in a mixture of dioxane/water (5 mL, 1:1) was heated at 180° C. for 50 minutes under microwave heating and a nitrogen atmosphere. AcOEt was added and the organic phase was washed with a saturated aqueous solution of Na2CO3. The organic layer was dried over MgSO4, was filtered and was concentrated. The crude compound was purified by flash chromatography with silica gel using cyclohexane/AcOEt (100:0 to 50:50) to yield 3-(4-fluorophenyl)-N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carboxamide (2.26 mmol, 833 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([O:13]C)=[O:12])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.O[Li].O>CO.O>[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=[O:12])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(Cl)cccc2s1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2c(Cl)cccc2s1
Yield: 99.6 %

Procedure:
Stir a mixture of methyl 4-chlorobenzo[b]thiophene-2-carboxylate (1.0 g, 4.44 mmol) and LiOH—H2O (0.56 g, 13.3 mmol) in MeOH (30 mL) and water (10 mL) at room temperature overnight. Concentrate the reaction mixture under vacuum and then dilute the residue with ice water (20 mL). Acidify the aqueous mixture with conc. HCl solution to pH=1. Extract the resultant mixture with EtOAc (15 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and evaporate under vacuum to afford 4-chlorobenzo[b]thiophene-2-carboxylic acid as a white solid (0.94 g, 100%). 1H NMR (400 MHz, CDCl3) δ 8.10-8.02 (m, 2H), 7.61-7.51 (m, 2H)
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:15]=1Cl)=[O:5])C.Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1>[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:4](=[O:5])[C:6]3=[N:7][NH:8][C:9]4[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=4[C:15]3=[N:26]2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nnc2c(c1Cl)CCCC2
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: Cc1ccccc1C
Product: O=c1c2n[nH]c3c(c-2nn1-c1ccc(F)cc1)CCCC3
Yield: 23 %

Procedure:
4-Chloro-5,6,7,8-tetrahydrocinnoline-3-carboxylic acid ethyl ester (0.5 g), 4-fluorophenylhydrazine hydrochloride (0.34 g) and H{umlaut over (u)}inig's base (0.73 ml) in xylene under nitrogen were heated under reflux for 2 h. The solid was collected by filtration, washed with diethyl ether, water and diethyl ether. The residue was recrystallised from ethanol to give the title compound (136 mg, 13%). δH (360 MHz; DMSO-d6) 1.83 (4H, m, CH2), 2.67 (2H, t, J=5.3 Hz, CH2), 2.72 (2H, t, J=5.3 Hz, CH2), 3.78 (3H, s, OCH3), 7.02 (2H, d, J=9 Hz, ArH), 8.06 (2H, d, J=9 Hz, ArH), m/z (ESP+) 285 (MH+). C15H13FN4O requires C, 63.37; H, 4.61; N, 19.71; found C, 62.96; H, 4.36; N, 19.48%.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5]([OH:7])=[O:6].[C:11](OC(C)C)(=O)C>CO>[ClH:1].[CH3:11][CH:4]([C:5]([OH:7])=[O:6])[C@@H:3]([C:8]([OH:10])=[O:9])[NH2:2]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: CC(=O)OC(C)C
Agent: Cl
Solvent: CO
Product: CC(C(=O)O)[C@H](N)C(=O)O
Reaction time: 6.5 h

Procedure:
To methanol (500 ml) at 25°, gaseous HCl (0.89 mole) was bubbled into the solution over about 0.5 hr. L-Aspartic acid (0.77 mole) was added rapidly, then the resulting solution was held at 25° C. for 6.5 hrs. The methanol was stripped with an aspirator maintaining the pot temperature below 35° C. The batch became fairly thick when 145 ml (115 g) of methanol remained. Isopropyl acetate (435 ml) was added in about 0.5 hr, then the slurry was cooled to 0°-5° C. and held for 0.5 hr. Solid β-methyl-L-aspartate hydrochloride was collected and washed with 100 ml of isopropyl acetate. Dry wt.=100.2 g (70.6%) m.p. 192°-4°.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH2:7]([Mg]Br)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>C(OCC)C.Cl[Ni]Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:20]([C:2]1[CH:6]=[CH:5][S:4][CH:3]=1)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: Brc1ccsc1
Reactant: CCCCCCCCCCCCCC[Mg]Br
Agent: Cl[Ni]Cl
Agent: Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCc1ccsc1
Yield: 75.9 %

Procedure:
To a mixture of 3-bromothiophene (81.5 g, 0.5 mol) and [1,3-bis(diphenylphosphino)propane]-dichloronickel(II) (dppp) in 300 mL of dry ethyl ether, tetradecylmagnesium bromide (560 mL, 0.56 mol) was added dropwise. The mixture was then refluxed overnight and cooled in an ice bath. A 5% HCl solution was added to destroy the unreacted Grignard reagents. The organic layer was separated from the water layer in a separation funnel. The ether solution was then washed with NaHCO3 solution (100 mL), brine (2×100 mL), and water (100 mL) and dried over anhydrous MgSO4. After the ether was removed, the organic residue was vacuum distilled (101° C./3 mmHg) to give 3-tetradecylthiophene: 85 g, yield 75.9%. 1H NMR: ä 7.23 (m, 1H), 6.93 (m, 1H), 2.62 (t, 2H), 1.64-1.26 (m, 16H), 0.88 (t, 3H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](Cl)[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=1>C1COCC1>[C:1]([C:5]1[N:6]=[C:7]([NH:26][CH2:25][CH2:24][C:21]2[CH:22]=[N:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CCN)cn1
Reactant: CC(C)(C)c1cn2c(=O)[nH]nc2c(Cl)n1
Solvent: C1CCOC1
Product: COc1ccc(CCNc2nc(C(C)(C)C)cn3c(=O)[nH]nc23)cn1

Procedure:
A solution of 50 mg of 6-tert-butyl-8-chloro-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one and 68 mg of 2-(6-methoxy-pyridin-3-yl)-ethylamine in THF (2 mL) was heated in a microwave apparatus (Emrys-Optimizer®, Personal Chemistry Inc., 2 Hampshire St., Suite 100, Foxboro, Mass.) at 150° C. for 10 min. The solvent was removed and the residue was purified by silica gel chromatography to afford the title compound as a white solid after trituration. MS (M+H+)=343.3.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](#[N:16])[CH:14]=[CH2:15]>C1C=CC=CC=1.CO>[C:13]([CH2:14][CH2:15][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:16]
Reactant: C=CC#N
Reactant: CCOC(=O)Cc1ccccc1
Solvent: c1ccccc1
Solvent: CO
Product: CCOC(=O)C(CCC#N)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 2-phenylacetate (5.00 g, 30.5 mmol) in benzene (50 mL) was added Triton-B (40% solution in methanol) (0.240 mL, 0.609 mmol) at 0° C. After stirring for 10 minutes, acrylonitrile (2.005 mL, 30.5 mmol) was added, and the reaction was allowed to warm to room temperature. The reaction was stirred for 3 hours, concentrated, loaded directly onto silica gel (GraceResolv High Resolution Flash Cartridge, 80 g) and eluted using a gradient of 5% to 40% ethyl acetate/hexanes over 40 minutes (flow rate=40 mL/minute). Concentration of product containing fractions provided the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.44-7.19 (m, 5H), 4.26-4.00 (m, 2H), 3.81-3.59 (m, 1H), 2.50-2.01 (m, 4H), 1.20 (t, J=7.1, 3H).
Reaction SMILES: [C:1]([C:3]1[O:7][C:6](Br)=[CH:5][CH:4]=1)#[N:2].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2([CH:21](B(O)O)CC[CH2:18]2)[C:10]1=[O:25].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>COCCOC.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>[CH3:18][C:11]1([CH3:21])[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:6]3[O:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:13]=2)[NH:9][C:10]1=[O:25]
Reactant: N#Cc1ccc(Br)o1
Reactant: O=C1Nc2ccccc2C12CCCC2B(O)O
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: COCCOC
Solvent: O
Product: CC1(C)C(=O)Nc2ccc(-c3ccc(C#N)o3)cc21
Temperature: 25 °C
Yield: 53.4 %

Procedure:
A solution of 5-cyano-2-bromofuran (0.5 g, 2.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.35 g, 49%) as an off-white solid. mp: 193-194° C.; 1H NMR (DMSO-d6) δ 10.6 (s, 1H), 7.7 (d, 2H, J=3.3 Hz), 7.6 (dd, 1H, J=1.6, 6.6 Hz), 7.1 (d, 1H, J=3.8 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.8 (m, 8H); MS [M−H]−=277.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH2:24][CH3:25])[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CO>[CH2:24]([C:15]1[NH:16][C:17]2[C:22]([C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[CH3:25]
Reactant: CCc1[nH]c2cc(F)ccc2c1C1=CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCc1[nH]c2cc(F)ccc2c1C1CCNCC1
Yield: 116.4 %

Procedure:
3-(1-Benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-ethyl-6-fluoro-1H-indole (1.4 g) is hydro-genated for 1 hour (r.t./1013 mbar) in the presence of 10% Pd/C catalyst (0.3 g) and methanol (25 ml). The catalyst is removed by filtration, the solvent evaporated and the residue washed with small portions of ether. 1.2 g (85%) of pure product is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([C:16]2([C:19]([O:21]CC)=[O:20])[CH2:18][CH2:17]2)[C@H:13]([F:24])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C@@H:13]([F:24])[C@@H:14]([C:16]2([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]2)[CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1([C@H]2CN(C(=O)OCc3ccccc3)C[C@H]2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1C[C@@H](F)[C@@H](C2(C(=O)O)CC2)C1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 92.1 %

Procedure:
1-Benzyloxycarbonyl-4-(S)-(1-ethoxycarbonyl-cyclopropyl)-3-(S)-fluoropyrrolidine (4.67 g, 13.92 mmol) was dissolved in ethanol (50 ml), and a 1 N sodium hydroxide aqueous solution (50 ml) was added dropwise to the resulting solution. The reaction solution was stirred at 40° C. for 1.5 hours and then ethanol was evaporated under reduced pressure. The resulting residue was mixed with water (50 ml) and washed with chloroform (100 ml), and the thus separated aqueous layer was acidified by adding dropwise 1 N hydrochloric acid and extracted with chloroform (200 ml×2) and then with diethyl ether (100 ml). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 3.94 g (92.1%) of the title compound as a colorless amorphous substance.