Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:43]=[CH:42][C:18]([C:19]([NH:21][C:22]3[C:23]4[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][C:24]=4[N:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:26]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>C(Cl)Cl>[ClH:1].[ClH:1].[ClH:1].[CH3:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:43]=[CH:42][C:18]([C:19]([NH:21][C:22]3[C:23]4[CH2:34][NH:33][CH2:32][C:24]=4[N:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:26]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCN(C)CC3)cc2)c2c1CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCN(C)CC3)cc2)c2c1CNC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 4N solution of hydrochloric acid in dioxane (122 ml, 488 mmol) was added dropwise to a stirred solution of 5-tert-butyl 1-ethyl 3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (19.5 g, 39.2 mmol), as prepared in Example 2, in dry DCM (240 ml); precipitation of a white solid occurred almost immediately. The resulting mixture was stirred at room temperature for 24 hours; after dilution with Et20 (100 ml), the solid was filtered, extensively washed with Et20, and dried under vacuum at 50° C. to give 20.1 g of the title compound, used in the next step without further purification. [M+H]+ 399.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:4]=2[N:3]=1.[Br-].[CH:19]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:21])[CH3:20]>>[CH2:16]([C:14]1[CH:13]=[CH:12][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:15]=1)[N:10]=[CH:9][CH:8]=[CH:7]3)[CH:19]([CH3:21])[CH3:20]
Reactant: Nc1nc2cc(C=O)ccc2c2cccnc12
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC(C)Cc1ccc2c(c1)nc(N)c1ncccc12

Procedure:
8-Isobutylbenzo[f][1,7]naphthyridin-5-amine was prepared from 5-aminobenzo[f][1,7]naphthyridine-8-carbaldehyde (from Example 87) with isopropyl(triphenyl)phosphonium bromide following the procedures described for Example 91 (wittig reaction) and Example 92 (reduction). 1H NMR (acetone-d6): δ 8.98 (dd, 1H), 8.88 (dd, 1H), 8.35 (d, 1H), 7.82 (dd, 1H), 7.44 (d, 1H), 7.18 (dd, 1H), 6.73 (br s, 2H), 2.63 (d, 2H), 2.04-1.94 (m, 1H), 0.94 (d, 6H). LRMS [M+H]=252.1.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=2)[CH2:14][C@H:13]1[O:26]C)=[O:10].B(Br)(Br)Br.C(Cl)Cl.O>C(Cl)Cl.C(#N)C.O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=2)[CH2:14][C@H:13]1[OH:26])=[O:10]
Reactant: CO[C@@H]1CN(c2ncc(C(=O)O)s2)CC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1[nH]c(C(=O)N[C@H]2CCN(c3ncc(C(=O)O)s3)C[C@H]2O)c(Cl)c1Cl
Temperature: 40 °C

Procedure:
Cis(±)2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2 -yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic acid (Example 35; 100 mg) was suspended in anhydrous DCM. BBr3/DCM (15 ml) was added and the mixture was heated at 40° C. for 18 h. The reaction mixture was cooled to −50° C. and water was added. The mixture was extracted with EtOAc and the organic phase was washed with water, dried over Na2SO4. The organic phase was concentrated in vacuo to yield a pale brown solid which was dissolved in acetonitrile/water mixture and was lyophilized (46 mg). MS (ES) MH+: 419 for C15H16Cl2N4O4S; NMR: 1.87 (m, 2H), 2.20 (s, 3H), 3-4 (brm, 6H), 6.9 (d, 1H), 7.51 (s, 1H), 12.19 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1.CN(C)C=O.C(Cl)(=O)C([Cl:22])=O>ClCCCl>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:22])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OCCCl)cc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cl)c1ccc(OCCCl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250-ml flask are combined 4-(2-chloroethoxy)benzoic acid (2.58 g, 12.9 mmol), dimethylformamide (0.2 ml) and 1,2-dichloroethane (50 ml). Oxalyl chloride (1.35 ml) is added dropwise and the reaction mixture stirred overnight at room temperature. The reaction becomes homogeneous after stirring several hours. After an overnight stir, the solvent is evaporated to dryness, and the solid product is redissolved in 1,2-dichloroethane (2×50 mL) and evaporated. The product is used as is in subsequent reactions.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][CH:17]([CH3:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20].[F:24][C:25]([F:37])([F:36])[CH:26]([CH3:35])[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>>[CH3:16][CH:17]([CH3:23])[CH2:18][S:19]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:32]([C:31]3[CH:33]=[CH:34][C:28]([O:27][CH:26]([CH3:35])[C:25]([F:24])([F:36])[F:37])=[CH:29][CH:30]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:21])=[O:20]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(Oc1ccc(N)cc1)C(F)(F)F
Product: CC(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(C)C(F)(F)F)cc3)C2=O)CC1

Procedure:
Off-white solid. MS (ESI): 463.18 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-methyl-propane-1-sulfonyl chloride, 4-(2,2,2-trifluoro-1-methyl-ethoxy)-aniline.
Reaction SMILES: [CH3:1][N:2]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[C:3](=[O:45])[C:4]1[CH:44]=[CH:43][CH:42]=[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]=2[C:22]2[CH:27]=[C:26]([C:28](=[O:41])[NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH:25]=[CH:24][N:23]=2)=[O:8])[CH:5]=1.C(N(CC)CC)C.[C:61](Cl)(=[O:63])[CH3:62]>ClCCl>[C:61]([N:51]1[CH2:52][CH2:53][N:48]([CH2:47][CH2:46][N:2]([CH3:1])[C:3](=[O:45])[C:4]2[CH:44]=[CH:43][CH:42]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)=[CH:12][C:11]=3[C:22]3[CH:27]=[C:26]([C:28](=[O:41])[NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=4)[CH:25]=[CH:24][N:23]=3)=[O:8])[CH:5]=2)[CH2:49][CH2:50]1)(=[O:63])[CH3:62]
Reactant: CN(CCN1CCNCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(CCN(C)C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Temperature: 0 °C
Yield: 34.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N1-methyl-N1-(2-(piperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenyl)-isophthalamide (150 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (3 mL), and triethylamine (63 mg, 0.62 mmol, 3.00 equiv). This was followed by dropwise addition of acetyl chloride (25 mg, 0.32 mmol, 1.50 equiv) with stirring at 0° C. The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched with 3 mL of water. The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×5 mL of sodium bicarbonate and 2×5 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (130 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 56.5 mg (38%) of a light yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.96 (d, J=5.1 Hz, 1H), 8.70 (d, J=9.0 Hz, 1H), 8.43 (s, 1H), 8.16˜8.08 (m, 3H), 7.87˜7.86 (m, 1H), 7.79˜7.56 (m, 7H), 4.71 (s, 2H), 4.00˜3.89 (m, 5H), 3.63˜3.52 (m, 1H), 3.23 (s, 3H), 2.17 (s, 3H), 2.01 (s, 1H), 1.81 (d, J=4.8 Hz, 1H). MS (ES, m/z): 770 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:4]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[N:15][CH:16]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([NH:40][CH2:2][C:3]3[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:4]=3[C:11]3[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[N:15][CH:16]=3)=[CH:36][CH:35]=2)=[CH:32][CH:33]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
Ethyl 3-(5-(2-(bromomethyl)-4,5-difluorophenyl)picolinamido)propanoate (115 mg, 0.27 mmol), 4′-chloro-[1,1′-biphenyl]-4-amine (110 mg, 0.54 mmol), and K2CO3 (74 mg, 0.54 mmol) were diluted with DMF (0.3 mL) and the resulting mixture was stirred at room temperature. After 2 h the resulting mixture directly purified via column chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[C:6]=1[CH2:7][OH:8]>CCO.C(O)(=O)C.[Fe]>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:5]2[C:6]([CH2:7][OH:8])=[C:2]([Cl:1])[N:3]=[C:4]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][CH:14]=1
Reactant: CCCCCCCc1nc(Cl)c(CO)n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCCCCc1nc(Cl)c(CO)n1Cc1ccc(N)cc1
Yield: 88.2 %

Procedure:
To a solution of 4-chloro-2-heptyl-5-hydroxymethyl-1-(4-nitrobenzyl)imidazole (1.00 g, 2.7 mmol) in EtOH (30 mL) and glacial acetic acid (5 mL) was added iron powder (2.5 g, 44.8 mmol). The mixture was stirred while being refluxed for 20 minutes. The solution was cooled, the iron was removed by filtration, and the solution was partitioned between EtOAc and 20% aq. K2CO3 (150 mL each). The organic phase was washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to afford 0.8 g yellow-orange oil. Flash chromatography (silica gel, 25 g; EtOAc/hexanes, 1:1) gave 0.74 g (80%) of yellow-orange oil. NMR (200 MHz, CDCl3) δ6.80-6.60 (ABq, 4H, 7 Hz, 32 Hz); 5.10 (s, 2H); 4.45 (s, 2H); 3.75-3.60 (m, 2H); 2.55 (t, 2H, 5 Hz); 1.75-1.65 (m, 2H); 1.30-1.15 (m, 8H); 0.90-0.80 (m, 3H). Mass Spec. 335.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[N+]([CH:12]=CC1SC=CC=1)([O-])=O.C=O.Cl>>[S:1]1[C:2]2[CH2:6][CH2:7][NH:8][CH2:12][C:3]=2[CH:4]=[CH:5]1
Reactant: NCCc1cccs1
Reactant: O=[N+]([O-])C=Cc1cccs1
Agent: C=O
Agent: Cl
Product: c1cc2c(s1)CCNC2

Procedure:
U.S. Pat. No. 4,906,756 to Lodewijk et al. proposes the reaction of 2-(2-thienyl)ethylamine, prepared from 2-(2-nitrovinyl)thiophene, with formaldehyde to produce the formimine, cyclizing the formimine with hydrochloric acid to produce 4,5,6,7-tetrahydrothieno[3,2,c]pyridine, and converting this compound to ticlopidine free base by reaction with o-chlorobenzylchloride. The free base is then converted to ticlopidine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[C:14]1[CH2:15][O:16][C@:17]2([CH2:23][CH2:22][CH2:21][NH:20][C@H:19]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1.C(O)(=O)C>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:11])[F:12])=[CH:5][C:4]=1[C@@H:14]1[CH2:18][C@@:17]2([CH2:23][CH2:22][CH2:21][NH:20][C@H:19]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:16][CH2:15]1
Reactant: COc1ccc(OC(F)(F)F)cc1C1=C[C@@]2(CCCN[C@H]2c2ccccc2)OC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(OC(F)(F)F)cc1[C@H]1CO[C@]2(CCCN[C@H]2c2ccccc2)C1
Reaction time: 16 h

Procedure:
A mixture of (5R,6S)-3-(2-methoxy-5-trifluoromethoxyphenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene (Example 2; 1.4 g), 10% palladium hydroxide/carbon (0.25 g) in methanol (90 ml) containing acetic acid (9 ml) was hydrogenated at 50 psi for 16 h. The solution was filtered, evaporated and the residue was crystallized twice from hexane to give the title compound. m.p. 91-104° C. 1H NMR (250 MHz, CDCl3) δ 7.50-7.54 (2H, m), 7.33-7.36 (3H, m),), 6.90 (1H, dd, J 8.9, 2.07 Hz), 6.68 (1H, d, J 8.9 Hz), 6.17 (1H, d, J 2.7 Hz), 4.08 (1H, t, J 7.8 Hz), 3.75 (1H, m), 3.69 (4H, s+d), 3.24 (1H, bd), 3.12 (1H, dd, J 10.3, 8.03 Hz), 2.82 (1H, td, J 12.4, 2.6 Hz), 2.16-1.80 (6H, m), and 1.55-1.64 (2H, m). m/z (ES+) 408 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(Cl)Cl.CO>[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH:21][C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)nnc(Cc2ccncc2)c1C
Reactant: Cc1cccc(N)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(Nc2nnc(Cc3ccncc3)c(C)c2C)c1

Procedure:
The compound is prepared starting from 0.070 g 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine and 0.129 g meta-methylaniline in the manner described in Example 82A. After heating for 20 h to 130° C., siginificant quantities of 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine are still present (TLC). For this reason, a further 0.129 g meta-methylaniline is added and heated for another 24 h to 130° C. Processing is in the manner described for Example 82A. Title compound of about 90% purity is obtained after FC in CH2Cl2/methanol 19/1; m.p. 68-90%°. 1H-NMR (250 MHz, CDCl3): δ=8.45 (d, 2H); 7.70 (t, 1H); 7.50 (s, 1H); 7.40-7.10 (m, 4H)); 6.90 (d, 1H); 6.15 (s, wide, 1H); 4.30 (s, 2H); 2.35 (s, 3H); 2.15 (s, 3H); 2.10 (s, 3H). ES-MS 305 (M+H). The starting material is prepared as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH:12]3[CH2:13][CH2:14][CH2:15][CH:11]3[N:10]([CH2:16][CH3:17])[C:9]2=[O:18])=[N:6][CH:7]=1.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)#[CH:20].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:16]([N:10]1[CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[N:8]([C:5]2[N:4]=[CH:3][C:2]([C:20]#[C:19][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:7][N:6]=2)[C:9]1=[O:18])[CH3:17]
Reactant: CCN1C(=O)N(c2ncc(Br)cn2)C2CCCC21
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1C(=O)N(c2ncc(C#Cc3ccccc3)cn2)C2CCCC21
Temperature: 75 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
In a microwave tube were dissolved 80 mg (0.26 mmol) of (rac)-1-(5-bromopyrimidin-2-yl)-3-ethylhexahydrocyclopenta[d]imidazol-2(1H)-one (Example 1, step 4) in 3 ml DMF. Argon was bubbled through the solution. Ethynylbenzene (57 μl, 53 mg, 0.52 mmol, 2 equiv.), Bis(triphenylphosphine)palladium(II) chloride (9 mg, 0.013 mmol, 0.05 equiv.), copper (I) iodide (1.5 mg, 7.7 μmol, 0.03 equiv.), triphenylphosphine (2.0 mg, 7.7 μmol, 0.03 equiv.) and 107 μl of triethylamine (78 mg, 0.77 mmol, 3 equiv.) were added. The dark brown solution was stirred at 75° C. overnight, adsorbed on silica and purified by flash chromatography (silica gel, 20 g, 0% to 80% EtOAc in heptane gradient) to yield 72.7 mg (85%) of the title compound as a brown solid, MS: m/e=333.3 (M+H+).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([O:12][C:13]2[C:18]3[C:19]([O:22][CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[N:20][O:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2].[CH:30]([C:32]1([C:38]([O:40][CH3:41])=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=O.C(C1(C(OC)=O)CCC1)=O>>[C:1]([O:4][CH2:5][C@@H:6]1[CH2:7][CH2:8][C@H:9]([O:12][C:13]2[C:18]3[C:19]([O:22][CH2:23][CH:24]4[CH2:25][CH2:26][N:27]([CH2:30][C:32]5([C:38]([O:40][CH3:41])=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH2:28][CH2:29]4)=[N:20][O:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1CC[C@@H](Oc2cccc3onc(OCC4CCNCC4)c23)CC1
Reactant: COC(=O)C1(C=O)CCOCC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(O[C@H]5CC[C@@H](COC(C)=O)CC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using (cis-4-{[3-(piperidin-4-ylmethoxy)-1,2-benzisoxazol-4-yl]oxy}cyclohexyl)methyl acetate (EXAMPLE 46, Step 3) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (EXAMPLE 18, Step 1) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([C:19]2[NH:23][N:22]=[N:21][N:20]=2)[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:14]([CH:31]([NH2:33])[CH3:32])[CH:13]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([C:19]2[NH:23][N:22]=[N:21][N:20]=2)[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:14]([CH:31]([NH:33][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:32])[CH:13]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1-c1nnn[nH]1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1-c1nnn[nH]1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (30 mg, 0.15 mmol), 1-[4-chloro-3′-fluoro-5-methyl-6-(1H-tetrazol-5-yl)biphenyl-2-yl]ethanamine (45 mg, 0.14 mmol), and N,N-diisopropylethylamine (0.047 mL, 0.27 mmol) in isopropyl alcohol (0.5 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C21H18ClFN9 (M+H)+: m/z=450.1. found: 450.1.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[NH2:19][CH2:20][C@@H:21]([C:23]1[CH:24]=[CH:25][C:26]([OH:34])=[C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=1)[OH:22]>>[OH:34][C:26]1[CH:25]=[CH:24][C:23]([CH:21]([OH:22])[CH2:20][NH:19][CH:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:5]4[NH:4][N:3]=[N:2][N:1]=4)=[CH:7][CH:8]=3)[CH2:13][CH2:14]2)=[CH:28][C:27]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(-c3nnn[nH]3)cc2)CC1
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(-c4nnn[nH]4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-[4-(1H-tetrazol-5-yl)-phenyl]-piperidine-4-one (which was obtained in Example 47) and N-[5-((1R)-2-amino-1-hydroxy- ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 73 as a white solid; mp >175° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.65 (m, 2H), 1.90-2.10 (m, 2H), 2.70-3.10 (m, 5H), 2.95 (s, 3H), 3.70-3.85 (m, 2H), 4.69 (dd, J=9.3, 3.0 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 6.97 (d, J=8.9 Hz, 2H), 7.06 (dd, J=8.3, 2.0 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.80 (d, J=8.9 Hz, 2H); MS (ES) m/z: 474.1 (MH+); HRMS Calcd. for C21H28N7O4S(MH+): 474.1918. Found: 474.1912.
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:8]=[N:9][N:10]([CH3:12])[CH:11]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([CH:33]=[O:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1.O>O1CCCC1.ClCCl>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C:31]([C@@H:33]([OH:34])[C:7]5[CH:8]=[N:9][N:10]([CH3:12])[CH:11]=5)([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C=O)C1
Reactant: Cn1cc(I)cn1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc([C@H](O)C23Cc4cnn(-c5ccc(F)cc5)c4C=C2CCN(C(=O)OC(C)(C)C)C3)cn1
Reaction time: 1 h

Procedure:
A second reaction was performed with inverse addition of n-butyl lithium. To a solution of 4-iodo-1-methyl-1H-pyrazole (157 mg, 0.755 mmol) in tetrahydrofuran (2 mL) was added n-butyl lithium (2.5 M in Hexanes) (312 μl, 0.780 mmol) at −78° C. The mixture was stirred at this temperature for 1 hour, then a solution of (R)-tert-butyl 1-(4-fluorophenyl)-4a-formyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (100 mg, 0.252 mmol) in tetrahydrofuran (1 mL) was added dropwise to the reaction mixture. The mixture was stirred at this temperature for 30 minutes. Water (6 mL) and dichloromethane (8 mL) were added and the phases were separated using a phase separator cartridge. The solvent was removed in vacuo to give an orange oil, with a similar composition to the previous reaction product according to LC/MS analysis.
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][NH:8][CH2:9]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[Cl:18][CH:19](Br)[CH2:20][CH3:21].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:18][CH2:19][CH2:20][CH2:21][N:8]1[CH2:9][CH:10]2[CH:5]([CH2:4][CH2:3][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:1]2)[CH2:6][CH2:7]1
Reactant: CCC(Cl)Br
Reactant: CC(C)(C)OC(=O)N1CCC2CCNCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2CCN(CCCCl)CC2C1
Temperature: 25 °C
Yield: 45.1 %

Procedure:
A mixture of tert-butyl octahydro-2,7-naphthyridine-2(1H)-carboxylate (320 mg, 1.33 mmol, 1 eq), chloro bromopropane (530 mg, 3.33 mmol, 2.5 eq) and K2CO3 (736 mg, 5.33 mmol, 4 eq) in acetone (25 mL) was heated to reflux overnight, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/MeOH) to afford the title compound as pale yellow oil (190 mg, 47%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 317.2 (M+1).