Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C([N+]([O-])=O)=C(N2CCN(CC(NC3SC=CN=3)=O)CC2)C(Br)=CN=1.Cl[C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH2:35])[C:29]=1[N+:36]([O-:38])=[O:37].CCN(C(C)C)C(C)C.[N:48]1[CH:53]=[CH:52][C:51]([CH:54]([N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH3:55])=[CH:50][CH:49]=1.Cl>CC(O)C>[Cl:34][C:33]1[C:28]([N:59]2[CH2:60][CH2:61][N:56]([CH:54]([C:51]3[CH:50]=[CH:49][N:48]=[CH:53][CH:52]=3)[CH3:55])[CH2:57][CH2:58]2)=[C:29]([N+:36]([O-:38])=[O:37])[C:30]([NH2:35])=[N:31][CH:32]=1
Reactant: CC(c1ccncc1)N1CCNCC1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccncc1)N1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1
Yield: 73 %

Procedure:
This was prepared using the same procedure as for 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide, but here using 4,5-dichloro-3-nitropyridin-2-amine (22 mg, 0.106 mmol), iPrOH (1 mL), DIPEA (0.2 mL) and 1-(1-(pyridin-4-yl)ethyl)piperazine.3×HCl (1.1 eq, 0.116 mmol, 35 mg). Filtration and washing as previously described gave the product (28 mg, 73%) as a yellow solid; δH (500 MHz, DMSO-d6) 1.30 (d, J=6.7 Hz, 3H, CHCH3), 2.42 (s, br, 2H, piperazine NCH2), 2.53 (s, br, 2H, piperazine NCH2), 3.05 (s, br, 4H, piperazine N(CH2)2), 3.54 (q, J=6.8 Hz, 1H, CHCH3), 6.94 (s, br, 2H, NH2), 7.34 (d, J=6.0 Hz, 2H, pyridine H-2 & H-6), 8.04 (s, 1H, chloropyridine H-6), 8.51 (d, J=6.0 Hz, 2H, pyridine H-3 & H-5);
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[C:26]([F:38])=[CH:25][C:23]=1[NH2:24]>>[NH2:24][C:23]1[C:22]([F:21])=[CH:28][C:27]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[C:26]([F:38])[CH:25]=1
Reactant: CC1(C)OB(c2cc(F)c(N)cc2F)OC1(C)C
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cc(F)c(N)cc3F)ccn2c1=O
Yield: 76.1 %

Procedure:
Methyl 8-(4-amino-2,5-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.71 mmol) and 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (667 mg, 2.06 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (500 mg, 75%). ESI-MS m/z: 407 (M+Na)+.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[C:8]([CH2:13][NH:14][C:15]([CH:17]2[CH2:22][CH2:21][N:20]3[C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=[C:19]3[CH2:18]2)=O)=[N:9][CH:10]=[CH:11][N:12]=1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[Cl:6][C:7]1[C:8]2[N:9]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]4[C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=[C:19]4[CH2:18]3)=[N:14][CH:13]=2)[CH:10]=[CH:11][N:12]=1
Reactant: O=C(NCc1nccnc1Cl)C1CCn2c(nnc2C(F)(F)F)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: FC(F)(F)c1nnc2n1CCC(c1ncc3c(Cl)nccn13)C2
Temperature: 70 °C
Yield: 44.7 %

Procedure:
POCl3 (1.7 g, 11.09 mmol) was added dropwise to a solution of N-((3-chloropyrazin-2-yl)methyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxamide (800 mg, 2.218 mmol) in CH3CN (4.4 mL) at 0° C., then DMF (0.11 mL) was added dropwise for 5 minutes at 0° C. The reaction was heated at 70° C. for overnight The reaction was poured into ice-water, then neutralized with aq. Na2CO3 to adjust to pH=8. The resulting mixture was extracted with DCM and the combined organic layer was washed with water, brine and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/THF=100/20) to afford 7-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine (0.34 g, yield 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[BrH:18].C1(S[C:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[NH:27])C=CC=CC=1>CO>[BrH:18].[O:11]=[C:10]1[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[NH:6][C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:26]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)=[NH:27])=[CH:3][C:4]1=2
Reactant: N=C(Sc1ccccc1)c1cccs1
Reactant: Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Agent: Br
Solvent: CO
Product: N=C(Nc1ccc2c(c1)C(=O)Nc1ccccc1N2)c1cccs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Amino-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one (Example 6, 54 mg, 0.24 mmol) was dissolved in methanol (10 mL) and thiophene-2-carboximidothioic acid phenyl ester hydrobromide (79 mg, 0.26 mmol) added. The reaction was stirred at room temperature for 4 hr. The solvent was evaporated and the residue recrystallized from a mixture of methanol and ether to give a yellow solid. The solid was washed several times with ether (84 mg, 0.20, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH2:10]Br)[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([I:20])[CH:14]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH2:10][O:19][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][C:15]=2[I:20])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1CBr
Reactant: Oc1ccc(Cl)cc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)cc1COc1ccc(Cl)cc1I
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred mixture of 4-Bromo-2-bromomethyl-benzonitrile Example 347A (1.00 g, 3.64 mmol) and 4-Chloro-2-iodo-phenol Example 347B (0.94 g, 3.69 mmol) in dry DMF (8.0 mL) under argon was added 95% NaH (103 mg, 4.08 mmol). The reaction mixture was stirred at room temperature for 2.5 hours and quenched with water (30 mL). The resulting mixture was extracted with ether (180 mL). The organic layer was washed with water (1×30 mL), 1N NaOH solution (1×30 mL) and brine (1×30 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 614 mg of crude 4-Bromo-2-(4-chloro-2-iodo-phenoxymethyl)-benzonitrile Example 347C which was used as is for the next transformation.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]2[CH2:14][N:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]4=[O:33])=[CH:19][C:18]=3[F:34])[CH2:16][CH:9]12)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[F:34][C:18]1[CH:19]=[C:20]([N:23]2[CH2:27][CH:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:21]=[CH:22][C:17]=1[N:15]1[CH2:16][CH:9]2[CH:10]([O:11][CH2:12][CH2:13][N:8]2[C:6](=[O:7])[CH2:5][OH:4])[CH2:14]1
Reactant: CC(=O)NCC1CN(c2ccc(N3CC4OCCN(C(=O)COC(C)=O)C4C3)c(F)c2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)NCC1CN(c2ccc(N3CC4OCCN(C(=O)CO)C4C3)c(F)c2)C(=O)O1
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To the compound 2-[6-(4-{5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-fluorophenyl)hexahydropyrrolo[3,4-b][1,4]oxazin-4(4aH)-yl]-2-oxoethyl acetate (590 mg) obtained from Example 06 above in methanol (15 ml) was added potassium carbonate (0.34 g) and stirred for overnight. The reaction mixture was filtered, concentrated and purified by column using 3% methanol in dichloromethane as eluant to yield the title compound (300 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[Cl:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:15]=1[C:16](O)=O>P(Cl)(Cl)(Cl)=O>[CH3:24][O:23][C:21]1[CH:20]=[CH:19][C:15]([C:16]2[NH:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=2)=[C:14]([O:13][CH2:12][CH2:11][CH2:10][Cl:9])[CH:22]=1
Reactant: Nc1ccncc1N
Reactant: COc1ccc(C(=O)O)c(OCCCCl)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc3cnccc3[nH]2)c(OCCCCl)c1

Procedure:
A mixture of 3,4-diaminopyridine and 2-(3-chloropropoxy)-4-methoxybenzoic acid in phosphorus oxychloride was stirred at reflux for 4 hours. The excess phosphorus oxychloride was then removed in vacuo and the residue carefully treated with water before basifying with dilute ammonia hydroxide and extracting with chloroform. The crude product was then dissolved in ethyl acetate, decolourised with charcoal and triturated with ethereal HCl to give the title compound m.p. 174°-176° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].Cl.[CH3:26][NH:27][CH3:28].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I.C(OCC)(=O)C>[Cl:24][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:27]([CH3:28])[CH3:26])[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Reactant: CNC
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C)c1cccc(C2CC(C)(C)c3cc(Cl)cc(C(=O)O)c3N2)c1
Temperature: 120 °C
Yield: 103.1 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.82 g, 1.0 mmol), dimethyl amine hydrochloride (0.65 g, 8 mmol), copper (I) iodide (230 mg, 1.2 mmol), N,N-dimethyl glycine hydrochloride (220 mg, 1.6 mmol) and potassium carbonate (0.83 g, 6 mmol) in dimethylsulfoxide (20 mL) was heated for 12 h at 120° C. After colling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (30% ethyl acetate/hexanes) to afford 6-chloro-2-(3-dimethylamino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (0.37 g, 51%) as a white solid: MS (ESI) M+1=359.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-])=O>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: CCO
Product: Nc1ccc(C(=O)O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 g (4.73 mmol) of 4-nitrophthalic acid is dissolved in 10 mL of anhydrous ethanol. The solution is stirred at room temperature and degassed under argon. 50 mg of palladium/charcoal (5%) are added in a single portion and hydrogen is bubbled into the solution. After 3 hours, the solution is filtered through Celite and then evaporated.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.BrC1C=NC2C(C=1)=CC=CC=2N1CCN(C)CC1.[Na+].[C:38]1([S:44]([O-])(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.[Cu]I.CO.ClCCl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[N:4]=[CH:3][C:2]([S:44]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:46])=[O:45])=[CH:11]3)[CH2:13][CH2:14]1
Reactant: O=S(=O)([O-])c1ccccc1
Reactant: CN1CCN(c2cccc3cc(I)cnc23)CC1
Agent: [Cu]I
Agent: CN1CCN(c2cccc3cc(Br)cnc23)CC1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCN(c2cccc3cc(S(=O)(=O)c4ccccc4)cnc23)CC1
Temperature: 120 °C
Reaction time: 40 h
Yield: 7 %

Procedure:
A 4:1 mixture of 3-iodo-8-(4-methyl-piperazin-1-yl)-quinoline (D2) and 3-bromo-8-(4-methyl-piperazin-1-yl)-quinoline (D1) (1.5 g), phenylsulfonic acid sodium salt, dihydrate (2.52 g, 12.6 mmol) and copper (I) iodide (2.4 g, 12.6 mmol) in N,N-dimethylformamide (25 ml) was stirred in an oil bath at 120° C. for 40 h under argon. To the reaction mixture, cooled to ambient temperature, was added 5% sodium hydrogen carbonate solution (100 ml) and dichloromethane (100 ml) with vigorous shaking. The insoluble material was filtered, washed with dichloromethane (3×20 ml) and discarded. The filtrate and washings were transferred to a separating funnel and the layers separated. The aqueous layer was extracted with dichloromethane (100 ml) and the combined organic extracts were washed with water (100 ml), dried (MgSO4) and concentrated in vacuo to an oil (0.9 g). The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane to afford an orange oil (0.28 g, Rf 0.11, methanol/dichloromethane 1:19). This material was further purified by passage through a strong cation exchange (SCX) column eluting firstly with methanol (fractions discarded) and then with methanol/aqueous ammonia-880 (10:1) to give the title compound (E1) as an orange oil (0.152 g, 0.41 mmol, 7% over two steps);
Reaction SMILES: [N:1]1([C:6]([O:8][C@H:9]2[CH2:14][C@H:13]([C:15]([NH:17][OH:18])=[O:16])[C@@H:12]([C:19]([N:21]3[CH2:26][CH:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)=[O:20])[N:11]([CH3:33])[CH2:10]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[N:1]1([C:6]([O:8][C@H:9]2[CH2:14][C@H:13]([C:15]([NH:17][OH:18])=[O:16])[C@@H:12]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)=[O:20])[N:11]([CH3:33])[CH2:10]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C[C@@H](OC(=O)N2CCCC2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CC=C(c2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CN1C[C@@H](OC(=O)N2CCCC2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCC(c2ccccc2)CC1
Yield: 99.1 %

Procedure:
A solution of (3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-yl pyrrolidine-1-carboxylate (5.0 mg, 0.000011 mol) TFA salt in 1 mL of MeOH was hydrogenated in the presence of 5% Pd/BaSO4, under a balloon pressure of hydrogen, for 2 h. After filtered off the catalyst, the filtration was concentrated to dry to give the product (5.0 mg, 100%). MS (ESI): (M+H)+=459.15.
Reaction SMILES: C1(C(=[N:14][C:15]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C2C=CC=CC=2)C=CC=CC=1.Cl>C(OCC)C.C([O-])(O)=O.[Na+]>[NH2:14][C:15]([CH2:21][CH3:22])([CH2:23][CH3:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(CC)(CC)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(N)(CC)CC
Reaction time: 15 h
Yield: 91.6 %

Procedure:
A solution of ethyl 2-[(diphenylmethylene)amino]-2-ethylbutanoate (20.79 g, 64.3 mmol), prepared in the previous step, in 200 mL of diethyl ether was cooled under nitrogen to ice-bath temperature. 1 N HCl (96 mL, 96.0 mmol) was added dropwise over 45 min. After the addition, the ice-bath was removed and the stirring continued for 15 h. The diethyl ether layer was separated and the aqueous layer was extracted two times with 50 mL of methylene chloride. The methylene chloride extracts were extracted two times with 40 mL of 2 N HCl. The aqueous layers were combined and concentrated under reduced pressure to give an oil. The oil was taken up in 200 mL of saturated NaHCO3 and stirred for 30 min. The aqueous layer was then extracted five times with methylene chloride. The organic extracts were dried (anhydrous MgSO4), filtered and the solvent removed under reduced pressure to give ethyl 2-amino-2-ethylbutanoate (9.3799 g, 92%) as a yellow liquid.
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O:8]CC)(=[O:7])[CH3:6].C(C1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:15][CH:14]=1)#N.[OH-].[Na+]>C(O)(=O)C>[C:23]1([C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]([C:5]([OH:8])=[O:7])=[CH:14][N:15]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N#Cc1cnc(-c2ccccc2)c2ccccc12
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cnc(-c2ccccc2)c2ccccc12

Procedure:
20.5 g of 1-phenylisoquinoline are dissolved in 100 ml of carbon tetrachloride, and 16 g of bromine are added at room temperature. The temperature is raised slowly and the mixture is kept under reflux for 1 hour. 7.9 g of pyridine in 10 ml of carbon tetrachloride are added dropwise to the boiling reaction mixture in the course of 2 hours, and the mixture is then heated at reflux temperature for a further 18 hours. The reaction solution is decanted off from the resinous precipitate and is concentrated, and the residue is crystallized from diisopropyl ether. 11.7 g of 4-bromo-1-phenylisoquinoline of melting point 123°-125° C. are obtained. 0.7 g of 4-bromo-1-phenylisoquinoline, 0.45 g of copper cyanide and 10 ml of dimethylformamide are heated at 160° C. for 6 hours. The reaction solution is decanted off, diluted with methylene chloride and washed with water. 0.75 g of crude product are isolated from the methylene chloride phase, and 0.2 g of 4-cyano-1-phenylisoquinoline of melting point 138°-140° is obtained from this crude product by column chromatography over silica gel using a 98:2 mixture of chloroform and ethyl acetate. 0.2 g of 4-cyano-1-phenylisoquinoline is heated with 10 ml of 20% strength sodium hydroxide solution at 100° C. for 4 hours. The solution is cooled and acidified with acetic acid. The precipitate is filtered off and dried. 0.18 g of 1-phenylisoquinoline-4-carboxylic acid of melting point 215°-217° is isolated.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+].O>O1CCCC1.O.CO>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:25])=[O:2])=[CH:16][CH:15]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
A solution of 2-(4-benzyloxy-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.38 g, 4.08 mmol) in tetrahydrofuran/water/methanol (10.2 ml, 3:1:1) was treated with a 2N aqueous sodium hydroxide solution (3.06 mL, 6.12 mmol). The reaction was stirred at 25° C. for 16 h. At this time, an additional amount of the 2N aqueous sodium hydroxide solution (3.06 mL, 6.12 mmol) was added. The reaction was stirred at 25° C. for an additional 24 h. At this time, the reaction mixture was poured into water and extracted into methylene chloride. The layers were separated. The aqueous layer was acidified to pH=1 with a 1N aqueous hydrochloric acid solution and was then extracted with a solution of methylene chloride/methano (90/10). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(4-benzyloxy-phenyl)-3-cyclopentyl-propionic acid (0.79 g, 60.2%) as a white solid: mp 112-114° C.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1(C)C=CC(S(O[CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:28][CH2:27]2)(=O)=O)=CC=1>C(O)C.O>[CH2:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][CH2:24][CH2:23][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:27][CH2:28]1)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)OCCCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)OCC

Procedure:
To a solution of sodium (5.8 g) in ethanol (300 ml) are added diethyl malonate (40 g) and 3-(1-benzyloxycarbonyl-4-piperidyl)propyl p-toluenesulfonate (90.5 g). The resulting mixture is refluxed for 2 hours with stirring, cooled, diluted with water (1 l) and extracted with ethyl acetate (500 ml). The extract is dried over magnesium sulfate and evaporated in vacuo to give ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)-2-ethoxycarbonylvalerate as an oil. To the stirred solution of this oil in ethanol (200 ml) is added dropwise a solution of sodium hydroxide (34 g) in water (200 ml). After the addition is complete, the mixture is diluted with water (300 ml) and extracted with a mixture of ether and petroleum ether (1:1, 300 ml). The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ethyl acetate (500 ml). The extract is washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield 5-(1-benzyloxycarbonyl-4-piperidyl)-2-carboxyvaleric acid as an oil. This oil is heated at 160°-170° C. for 45 minutes with stirring to give 5-(1-benzyloxycarbonyl-4-piperidyl)valeric acid (50 g) as an oil.
Reaction SMILES: C(OC([N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9][CH2:10][C:11]1[NH:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1)=O)(C)(C)C.[CH:29]1(B(O)O)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Na+].[Na+].N1C=CC=CC=1C1C=CC=CN=1>ClC(Cl)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:29]1([N:15]2[C:11]([CH2:10][CH2:9][NH:8][C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[N:12][C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:14]2)[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N(CCc1nc(-c2ccccc2)n[nH]1)C(=O)OC(C)(C)C
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCc1nc(-c2ccccc2)nn1C1CC1
Temperature: 85 °C
Reaction time: 40 h
Yield: 154.7 %

Procedure:
A suspension of 5-[2-bis(tert-butoxycarbonyl)aminoethyl]-3-phenyl-[1,2,4]triazole (218 mg, 561 μmol, example 22, step 1), cyclopropylboronic acid (192.8 mg, 2.24 mmol) and sodium carbonate (119 mg, 1.12 mmol) in dichloroethane (4 mL) was evacuated and backfilled with argon. A hot suspension of copper (II) acetate (102 mg, 561 μmol) and 2,2′-bipyridine (87.6 mg, 561 μmol) in dichloroethane (1.5 mL) was added and the reaction mixture was stirred at 85° C. for 40 h. The reaction mixture was cooled to RT, filtered and washed with dichloromethane. The filtrate was extracted with water (2×20 mL), dried over MgSO4, filtered and evaporated to give 285 mg of green oil. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as colorless viscous oil (105 mg, 320 μmol, 57.0%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:18][CH3:19])[C:15]([OH:17])=O)=[CH:8][CH:7]=2)#[CH:2].ON1C2N=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:52][C:53]([CH3:59])([CH2:56][O:57][CH3:58])[CH2:54][OH:55].[NH4+].[Cl-]>CC#N.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:18][CH3:19])[C:15]([NH:52][C:53]([CH2:56][O:57][CH3:58])([CH3:59])[CH2:54][OH:55])=[O:17])=[CH:8][CH:7]=2)#[CH:2]
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)O)cc2c1
Reactant: COCC(C)(N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(CO)COC)cc2c1
Yield: 35.4 %

Procedure:
(3-Ethynyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid (413 mg), 1-hydroxy-7-azabenzotriazole (HOAT) (267 mg), O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (630 mg), 2-amino-3-methoxy-2-methyl-propan-1-ol (180 mg) and triethylamine (0.75 ml) in dry CH3CN (20 ml) were stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate and poured on sat. aq. NH4Cl. The water phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (cyclohexane/ethyl acetate 1:1) to give as a yellowish oil 2-(3-Ethynyl-quinolin-6-yloxy)-N-(2-hydroxy-1-methoxymethyl-1-methyl-ethyl)-2-methylsulfanyl-acetamide (200 mg) as a mixture of diastereoisomers.