Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:20](=[O:32])[N:19]2[CH3:33])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:21]2[CH2:22][CH:18]([CH2:17][CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:34])=[O:3])=[CH:14][CH:13]=3)[N:19]([CH3:33])[C:20]2=[O:32])=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CN2CC(CCOc3ccc(OC(C)(C)C(=O)O)cc3)N(C)C2=O)cc1
Yield: 78.9 %

Procedure:
A solution of 2-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (0.198 g, 0.421 mmol) in ethanol (10 mL) was treated with aqueous 5 N NaOH (1 mL) and heated to reflux 1.5 h. The reaction mixture was cooled, the solvent removed in vacuo. The resultant residue was acidified with aqueous 1 N HCl (10 mL) and extracted with Et2O. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford 0.147 g (79%) 2-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid. MS (ES+) Calc'd for C24H31N2O6 (M+1) 443. Found m/z 443 (100%). 1H NMR.
Reaction SMILES: [OH-].[Na+].Cl.[N:4]1([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17]Cl)[C:11]=2[Cl:19])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[F:20][C:21]([F:36])([O:25][C:26]1[CH:35]=[CH:34][C:29]2[N:30]=[C:31]([SH:33])[NH:32][C:28]=2[CH:27]=1)[CH:22]([F:24])[F:23]>C(O)C>[N:4]1([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][S:33][C:31]3[NH:30][C:29]4[CH:34]=[CH:35][C:26]([O:25][C:21]([F:36])([F:20])[CH:22]([F:24])[F:23])=[CH:27][C:28]=4[N:32]=3)[C:11]=2[Cl:19])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: Cc1cnc(CCl)c(Cl)c1N1CCCCC1
Reactant: FC(F)C(F)(F)Oc1ccc2nc(S)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc(CSc2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c(Cl)c1N1CCCCC1

Procedure:
5N Sodium hydroxide (2 ml) was added to a stirred suspension of 4-piperidino-3-chloro-5-methyl-2-chloromethylpyridine hydrochloride (1.6 g) and 5-(1,1,2,2-tetrafluoroethoxy)-2-mercaptobenzimidazole (1.5 g) in ethanol at room temperature. After standing over night an additional quantity of sodium hydroxide (1 ml) was added and after a further 1 hour the mixture was evaporated at reduced pressure. The residue was chromatographed (silica gel chloroform/methanol 2%) and crystallised from acetonitrile to give 2-(4-piperidino-3-chloro-5-methyl-2-pyridylmethylthio)-5-(1, 1,2,2-tetrafluoroethoxy)-(1H)-benzimidazole, 1.66 g, m.p. 170°-71°.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=3F)=[N:14]/[OH:15])=[C:9]([CH2:25][CH2:26][CH3:27])[CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=4[O:15][N:14]=3)=[C:9]([CH2:25][CH2:26][CH3:27])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1/C(=N/O)c1cc(OC)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(OC)cc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of the oxime from Step 4 (1.4 g, 3.3 mmol) and cesium carbonate (2.1 g, 6.7 mmol) in DMF (20 mL) was stirred at 80° C. for 18 h. The reaction was diluted with ethyl acetate and washed with water. The crude product was purified by chromatography on silica gel to give the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]=[CH:15][NH:16][C:17](=O)[C:18]=3[N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].P(Cl)(Cl)([Cl:23])=O.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[Cl:23][C:17]1[C:18]2[N:19]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([CH3:1])[CH:3]=3)[CH:11]=[CH:12][C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2ccc3nc[nH]c(=O)c3n2)cc1C
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1C
Yield: 74.5 %

Procedure:
To a suspension of 6-(3-methyl-4-methoxyphenyl)-pyrido[3,2-d]pyrimidin-4(3H)one (1.41 mmole) in toluene (80 ml) was added phosphorus oxychloride (4.23 mmole) and 2,6-lutidine (4.23 mmole). The reaction mixture was refluxed for 16 hours until a black solution was obtained. After evaporation to dryness, the residue was redissolved in ethyl acetate and extracted with a saturated sodium bicarbonate solution. The combined organic layers were evaporated in vacuo. The residue was purified by silica gel column chromatography (the mobile phase being a ethylacetate/hexane mixture in a ratio gradually ranging from 2:8 to 3:7), resulting in the pure title compound (300 mg, yield 74%) which was characterized by its mass spectrum as follows: MS (m/z): 287 ([M+H]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[N:29]([CH3:30])[C:28](=[O:31])[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([N+:32]([O-])=O)[CH:26]=4)[N:21]=3)[CH3:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1>[Cl-].[Cl-].[Zn+2].C(O)C>[NH2:32][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([CH:18]([N:15]1[CH2:14][CH2:13][N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH2:17][CH2:16]1)[CH3:19])[N:29]([CH3:30])[C:28]2=[O:31]
Reactant: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc4ccc([N+](=O)[O-])cc4c(=O)n3C)CC2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc4ccc(N)cc4c(=O)n3C)CC2)cc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
To the 15 ml ethanol solution of 2-{1-[4-(4-Methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3-methyl-6-nitro-3H-quinazolin-4-one (560.0 mg, 1.14 mmol) was added ZnCl2 (1.08 g, 5.7 mmol). The reaction was refluxed for 2 hours with vigorous agitation by a magnetic stirrer. The mixture was cooled to room temperature, the solvent was removed by reduce pressure and extracted with Na2CO3 aqueous and ethyl acetate, dried over anhydrous MgSO4, and concentrated by rotary evaporation. Purification was accomplished by HPLC (Gilson-215, 0.035% TFA in acetonitrile and 0.05% water as mobile phase). The product was collected and dried under reduced pressure to give 6-Amino-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3-methyl-3H-quinazolin-4-one (Yield 427.3 mg, 81.9%). 1H NMR (400 MHz, DMSO-d6): δ 1.72 (d, 3H, J=6.57 Hz), 3.44-3.29 (m, 4H), 3.62-3.50 (m, 4H), 3.65 (s, 3H), 3.93 (s, 3H), 4.70 (q, 1H, J=12.88, 6.82 Hz), 7.19 (d, 2H, J=8.84 Hz), 7.49 (dd, 1H, J=8.84, 2.53 Hz), 7.65 (d, 1H, J=8.59 Hz), 7.81-7.77 (m, 3H). MS m/z calc. 457.2 found (ESI); 458.2 (M+1)+. Retention time 2.28 minutes.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:36])[CH:13]([C:20]2[N:21]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:22]=[C:23]3[C:28]=2[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:7]([F:37])[CH:6]=1)C.[OH-].[Li+]>C1COCC1.CO>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([N:21]2[C:20]([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:38])=[O:3])=[CH:6][C:7]=3[F:37])=[O:36])=[C:28]3[C:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:22]2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 7.2, 4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid ethyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as off-white oil. MS: m/e=510.3 [M+H+].
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:4](=[O:5])[CH:3]([O:8][CH3:9])[O:2][CH3:1])=[CH:13][CH:12]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)C(OC)OC
Product: COC(OC)C(=O)NCc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
Into a sealable tube were added methyl dimethoxyacetate (0.98 g, 7.3 mmol) and 4-fluorobenzylamine (0.91 g, 7.3 mmol); mixture was stirred at 60° C. for 2 days. The compound was purified by column chromatography on silica gel (10 g/70 mL prepacked cartridge, eluting with 5% EtOAc in hexanes→5% MeOH in hexanes), affording the title compound. HPLC: tR=2.58 min. (ZQ2, polar—5 min.). MS (ES+): m/z=249.92 (24) [MNa+], 227.91 (100) [MH+].
Reaction SMILES: C([N:14]1[CH2:17][C:16]([NH:21][CH3:22])([C:18]([NH2:20])=[O:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:23]>CO.[OH-].[OH-].[Pd+2]>[ClH:23].[CH3:22][NH:21][C:16]1([C:18]([NH2:20])=[O:19])[CH2:17][NH:14][CH2:15]1
Reactant: CNC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CNC1(C(N)=O)CNC1

Procedure:
To a suspension of 1-benzhydryl-3-methylaminoazetidine-3-carboxylic acid amide (I-2A-69b; 13.5 g, 45.8 mmol) in methanol (90 ml) was added concentrated aqueous HCl (8.0 ml, 96 mol), dropwise, to give a homogeneous solution. After the addition of 20% Pd(OH)2 on carbon (50% water; 4.1 g), the mixture was placed on a Parr® shaker and then reduced (50 psi H2) at room temperature for 7 hours. The mixture was filtered through a pad of Celite®, washing with a copious amount of 9:1 methanol/water, and then 9:1 tetrahydrofuran/water until no product eluted (determined with ninhydrin stain). The filtrate was then concentrated, in vacuo, and the residue was then triturated from diethyl ether to give I-2A-90a (9.3 g, quantitative) as a brown solid: +APcl MS (M+1) 129.9; 1H NMR (400 MHz, CD3OD) δ 4.50 (d, J=12.0 Hz, 2H), 4.43 (d, J=12.9 Hz, 2H), 2.64 (s, 3H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][CH:15]=1)=[O:13])[CH3:10]>C(O)(=O)C>[CH2:9]([O:11][C:12]([C:14]1[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:15]=1[Cl:1])=[O:13])[CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1csc(CC)c1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)sc1Cl
Reaction time: 8 h
Yield: 69.9 %

Procedure:
N-Chlorosuccinimide (0.8 g, 5.9 mmol) was added to a solution of 5-ethyl-thiophene-3-carboxylic acid ethyl ester (1 g, 5.43 mmol) in acetic acid (10 mL) and stirred overnight. The reaction was filtered and the solvent removed under vacuum. The product was purified by flash chromatography on silica, eluting with 0%-100% t-butylmethyl ether in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.83 g). 1H NMR (400 MHz, CHCl3-d): δ 7.05 (s, 1H), 4.3 (q, 2H), 2.75 (q, 2H), 1.4 (t, 3H), 1.3 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]([C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][C:32]([N:34]1[CH:39]([C:40]2[NH:44][C:43]3[CH:45]=[C:46]([C:49]4[CH:54]=[CH:53][C:52](B5OC(C)(C)C(C)(C)O5)=[CH:51][CH:50]=4)[CH:47]=[CH:48][C:42]=3[N:41]=2)[CH:38]2[CH2:64][CH:35]1[CH2:36][CH2:37]2)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C.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>[C:27]([O:31][C:32]([N:34]1[CH:39]([C:40]2[NH:44][C:43]3[CH:45]=[C:46]([C:49]4[CH:54]=[CH:53][C:52]([C:23]5[CH:22]=[CH:21][C:20]([C:17]6[NH:16][C:15]([CH:14]7[CH2:13][C:10]8([CH2:11][CH2:12]8)[CH2:9][N:8]7[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[N:19][CH:18]=6)=[CH:25][CH:24]=5)=[CH:51][CH:50]=4)[CH:47]=[CH:48][C:42]=3[N:41]=2)[CH:38]2[CH2:64][CH:35]1[CH2:36][CH2:37]2)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1nc2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]c5c4)cc3)cc2)[nH]1
Temperature: 90 °C
Yield: 30 %

Procedure:
A mixture of 6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (101 mg, 0.243 mmol, 1 eq.), 3-{6-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-benzoimidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (150 mg, 0.291 mmol, 1.2 eq.), tetrakis(triphenylphosphine)palladium (5%, 17 mg) and 2M potassium carbonate aqueous solution (5 eq., 0.73 mL) in 1.5 mL DME was heated to 90° C. under Are overnight. The reaction mixture was cooled and dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexane) to give 3-(6-{4′-[2-(5-tert-Butoxycarbonyl-5-aza-spiro[2.4]hept-6-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (53 mg, yield 26%). LCMS-ESI−: calc'd for C44H50N6O4: 726.91. Found: 727.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([N+:23]([O-])=O)[C:11]3[C:15]([CH:16]=2)=[N:14][N:13]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:12]=3)[CH:5]=[CH:6][CH:7]=1>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH2:23])[C:11]3[C:15]([CH:16]=2)=[N:14][N:13]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:12]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2cc([N+](=O)[O-])c3cn(C4CCCCO4)nc3c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2cc(N)c3cn(C4CCCCO4)nc3c2)c1

Procedure:
6-(3-Methylphenyl)-4-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (422 mg, 1.25 mmol) was dissolved in ethyl acetate (25 ml) and reduced using the H-cube (available from ThalesNano) with a Pd/C catalyst cartridge at a pressure of up to 80 bar. The solvent was removed in vacuo to give the title compound, 286 mg.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)[C@@H:6]([C@H:8]1[CH2:17][C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2Br)[CH2:10][N:9]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[OH:7])(=[O:3])[CH3:2].ClCCl.[I-].[CH2:41]([Zn+])[C:42]([CH3:45])([CH3:44])[CH3:43].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:1]([NH:4][C@@H:5]([CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)[C@@H:6]([C@H:8]1[CH2:17][C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:10][N:9]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[OH:7])(=[O:3])[CH3:2]
Reactant: CC(C)(C)C[Zn+]
Reactant: COc1ccc(Br)c2c1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(C)=O)C2
Agent: [Cl-]
Agent: [I-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(CC(C)(C)C)c2c1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(C)=O)C2
Temperature: 25 °C
Reaction time: 6 h
Yield: 46 %

Procedure:
Dissolve tert-butyl 3(R)-[(1S,2S)-2-(acetylamino)-3-(3,5-difluorophenyl)-1-hydroxypropyl]-5-bromo-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (46.0 mg, 0.0808 mmol) in tetrahydrofuran (1.00 mL) in a sealed tube flushed with nitrogen. Add [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (3.3 mg, 0.0040 mmol) and 0.500 M of neopentyl zinc iodide in tetrahydrofuran (0.808 mL) dropwise at room temperature. Stir the resulting green solution at room temperature for six hours. Heat to 50° C. for three days. Add saturated ammonium chloride solution (2 mL) and dilute with ethyl acetate (30 mL). Add water (10 mL) and separate the layers. Extract the aqueous layer (1×30 mL) with ethyl acetate. Combine the organic layers and dry over magnesium sulfate. Purify (Biotage medium pressure chormatography eluting with 1.5% methanol:dichloromethane) to give desired product (21.8 mg, 46%) as an off-white foam.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[F:32][C:17]([F:16])([F:33])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26]([N:2]2[CH2:3][CH2:4][CH:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=3)[CH2:6][CH2:7]2)=[O:27])[N:19]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: N#Cc1ccc(C2CCNCC2)nc1
Agent: Cl
Product: N#Cc1ccc(C2CCN(C(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)CC2)nc1
Yield: 30 %

Procedure:
This compound was synthesized from 6-(piperidin-4-yl)nicotinonitrile hydrochloride and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (50 mg, yield 30%). 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J=2.0 Hz, 1H), 8.20-8.19 (m, 2H), 7.95-7.92 (dd, J=8.2 Hz, 2.1 Hz, 1H), 7.67-7.59 (m, 2H), 7.33 (d, J=8.3 Hz, 1H), 4.92 (m, 1H), 3.91 (m, 1H), 3.24 (m, 1H), 3.09 (m, 1H), 2.97 (m, 1H), 2.09 (m, 1H), 1.94-1.83 (m, 3H). MS (ESI) m/z: Calculated for C21H16F3N6O2: 427.13. found: 428.2 (M+H)+
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C(N(C(C)C)CC)(C)C.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C(O)C>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]cnc23)CC1

Procedure:
To a solution of 6-chloropurine [CAS No. 87-42-3] (7.73 g) in ethanol (100 mL), diisopropylethylamine (26.1 mL) and piperazine-1-carboxylic acid t-butylester (11.16 g) were added, and this was heated under reflux for 16 hours. The solvent was removed under reduced pressure, and the residue was suspended in water (200 mL). The precipitate was collected by filtration, and then washed twice with 50 mL of water and twice with 50 mL of t-butyl methyl ether to give the title compound (13.99 g).
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].Br[C:6]1[CH:7]=[C:8]2[C:21]3[C:11]([CH2:12][C@@H:13]4[C@@H:18]([C:19]=3[CH:20]=1)[CH2:17][C@H:16]([NH:22][C:23](=[O:29])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:15][N:14]4[CH2:30]CC)=[CH:10][N:9]2[Si](C(C)(C)C)(C)C>>[CH2:27]([N:24]([CH2:25][CH3:26])[C:23]([NH:22][C@H:16]1[CH2:17][C@H:18]2[C@@H:13]([CH2:12][C:11]3[C:21]4[C:8](=[CH:7][C:6]([CH:1]([CH3:3])[CH3:2])=[CH:20][C:19]2=4)[NH:9][CH:10]=3)[N:14]([CH3:30])[CH2:15]1)=[O:29])[CH3:28]
Reactant: CC(C)I
Reactant: CCCN1C[C@@H](NC(=O)N(CC)CC)C[C@@H]2c3cc(Br)cc4c3c(cn4[Si](C)(C)C(C)(C)C)C[C@H]21
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(C(C)C)cc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
With isopropyl iodide and 3-(13-bromo-1-tert-butyldimethylsilyl-6-n-propyl-8α-ergolinyl)-1,1-diethylurea:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>C1(C)C=CC=CC=1>[CH2:15]([N:17]([CH2:18][CH3:19])[CH2:2][CH2:3][N:4]1[CH:8]([OH:9])[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]1[OH:14])[CH3:16]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CCNCC
Solvent: Cc1ccccc1
Product: CCN(CC)CCN1C(O)c2ccccc2C1O

Procedure:
25.4 g (0.10 mol) of N-(2-bromoethyl)phthalimide were dissolved together with four times the molar quantity of diethylamine (29.2 g; 0.40 mol) in 500 ml of toluene and refluxed for 8 hours. After the reaction, excess diethylamine and the solvent were removed under a vacuum in a rotary evaporator. The residue was combined with tert-butyl methyl ether and the precipitated salt removed by filtration. The ether phase was then completely evaporated off. Yield: 21.0 g (85.4%).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:73])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:71])[C:57]4[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[CH:59][CH:58]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:72])[C:36]([O:38]C)=[O:37]>>[CH3:73][CH:34]([CH3:33])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:71])[C:57]4[CH:58]=[CH:59][C:60]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[CH:61][CH:62]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:72])[C:36]([OH:38])=[O:37]
Reactant: CCCCCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)cc2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CCCCCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)cc1
Yield: 82 %

Procedure:
The compound of example 172 was prepared analogous to compound of example 98 by hydrolysis of compound of example 171.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1>CCOCC>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:22])=[CH:16][CH:15]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: C1CCNCC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(Cc1ccc(F)cc1)N1CCCCC1

Procedure:
A well stirred mixture of 111.8 g of piperidine, 103 g of pyridine and one liter of anhydrous ether was treated dropwise with 220 g of freshly distilled 4-fluorophenyl acetyl chloride. This mixture was stirred overnight, then filtered and the filtrate washed successively with water twice, 0.1N sodium hydroxide twice, 0.1N hydrochloric acid twice, water and saturated sodium chloride, then dried in vacuo. The residue was distilled giving a yellow liquid which crystallized on standing, giving 245 g of N-(4-fluorophenylacetyl)piperidine.
Reaction SMILES: FC1C=CC=CC=1C([O:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=O.[OH-].[Na+].Cl>CO>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([C@@H:10]2[CH2:11][CH2:12][C@H:7]([OH:6])[CH2:8][CH2:9]2)=[CH:18][CH:17]=1
Reactant: O=C(O[C@H]1CC[C@@H](c2ccc(Br)cc2)CC1)c1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O[C@H]1CC[C@@H](c2ccc(Br)cc2)CC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
(cis)-4-(4-Bromophenyl)cyclohexyl 2-fluorobenzoate (110 mg) is dissolved in methanol (2 mL), treated with aqueous NaOH solution (1 M, 875 μL) and the mixture is stirred for 48 hours at room temperature and for 5 hours at 40° C. Then the mixture is neutralized with hydrochloric acid (1 M), partitioned between ethylacetate and brine. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→70:30) to give the title compound. LC (method 1): tR=1.04 min; Mass spectrum (ESI+): m/z=237 [M−H2O+H]+.