Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[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.C(O)C>[CH2:1]([CH:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:34])([F:33])[F:22])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(CN2CCOC(Cc3ccccc3)C2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
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: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCOC(Cc3ccccc3)C2)cc1
Temperature: 120 °C

Procedure:
The above compound could be made in the following manner: 1 eq. of 2-Benzyl-4-(4-bromo-benzyl)-morpholine could be combined with 1.5 eq. of 2-(Trifluoromethyl)phenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine)palladium(0), 6.7 eq. of 2M sodium carbonate solution, toluene and ethanol. The reaction mixture could be heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture could be filtered through Celite and concentrated in vacuo. The residue could be diluted with water and extracted with ethyl acetate. The combined organic phases could be washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material could be purified by flash chromatography to afford product.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH:33]([CH3:36])[CH2:34][OH:35]>>[CH3:31][N:2]([CH3:1])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][CH:33]([CH3:36])[CH2:34][OH:35])=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: CC(N)CO
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (±)-2-amino-1-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.23 (1H, d, J=8 Hz), 8.50 (1H, s), 7.77 (1H, s), 7.32 (2H, dd, J=8.4, 5.7 Hz), 7.12 (2H, t, J˜9 Hz), 5.12 (2H, m), 4.98 (1H, t, J=5 Hz), 4.11 (2H, s), 4.03 (1H, m), 3.45 (2H, m), 3.12 (3H, s), 2.82 (3H, s), 1.15 (3H, d, J=7 Hz); HRMS calcd for C23H25FN4O5+H+: 457.18817. Found: 457.18872.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:5]=1[NH2:6].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:3][C:2]([F:13])([F:12])[F:1])[CH:10]=1
Reactant: OB(O)c1ccccc1F
Reactant: Nc1ccc(Br)cc1OC(F)(F)F
Product: Nc1ccc(-c2ccccc2F)cc1OC(F)(F)F
Yield: 57.1 %

Procedure:
The title compound (0.294 g) was prepared from 2-trifluoromethoxy-4-bromo aniline (0.5 g, 1.9 mmol) and 2-fluorophenylboronic acid (0.345 g, 2.5 mmol) as a yellow liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.47 (td, J 1.2, 4.7, 1H), 7.33-7.20 (m, 5H), 6.89 (d, J 8.8, 1H), 5.62 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([N:12]([CH3:22])[C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])[CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C[Si](Cl)(C)C.Cl[C:29](OC1C=CC([N+]([O-])=O)=CC=1)=[O:30].Cl.[Cl:42][C:43]1[CH:44]=[C:45]([C@:49]([C@@H:57]2[CH2:62][CH2:61][CH2:60][NH:59][CH2:58]2)([OH:56])[CH2:50][CH2:51][CH2:52][CH2:53][O:54][CH3:55])[CH:46]=[CH:47][CH:48]=1>C(Cl)Cl.CCN(CC)CC>[Cl:42][C:43]1[CH:44]=[C:45]([C@:49]([C@@H:57]2[CH2:62][CH2:61][CH2:60][N:59]([C:29]([NH:1][CH2:2][CH:3]([N:12]([CH3:22])[C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])=[O:14])[CH2:4][C:5]3([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)=[O:30])[CH2:58]2)([OH:56])[CH2:50][CH2:51][CH2:52][CH2:53][O:54][CH3:55])[CH:46]=[CH:47][CH:48]=1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN(C(=O)OCC[Si](C)(C)C)C(CN)CC1(O)CCCCC1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)NCC(CC2(O)CCCCC2)N(C)C(=O)OCC[Si](C)(C)C)C1
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of 1-(3-amino-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propyl)cyclohexanol (21 mg, 0.064 mmol) in CH2Cl2 (2 mL) was added Et3N (0.2 mL) and TMSCl (13.9 mg, 16 μL, 0.13 mmol). The resulting solution was stirred for 1 h and evaporated under vacuum The residue was dissolved in CH2Cl2 (2 mL) and pyridine (0.05 mL) was added, followed by 4-nitrophenyl chloroformate (15 mg, 0.077 mmol). The solution was stirred for 30 min and (S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol hydrochloride (27 mg, 0.077 mmol) was added. The resulting mixture was stirred for 10 min and evaporated. The residue was purified by preparative HPLC to give (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propyl)piperidine-1-carboxamide (22 mg, 51%). MS m/z 668 (M+H+).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:21]=[C:20]3[C:12]([C:13]4[C:14]([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([N:31]6[CH2:39][C:38]7[C:33](=[CH:34][C:35]([CH3:40])=[CH:36][CH:37]=7)[C:32]6=[O:41])[C:26]=5[CH3:42])=[CH:15][CH:16]=[C:17]([C:22]([NH2:24])=[O:23])[C:18]=4[NH:19]3)=[CH:11][CH:10]=2)[CH2:4][O:3]1.C(O)(C(F)(F)F)=O>CO.CS(C)=O>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[C:14]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([N:31]5[CH2:39][C:38]6[C:33](=[CH:34][C:35]([CH3:40])=[CH:36][CH:37]=6)[C:32]5=[O:41])[C:26]=4[CH3:42])=[CH:15][CH:16]=[C:17]([C:22]([NH2:24])=[O:23])[C:18]=3[NH:19]2)=[CH:11][CH:10]=1
Reactant: Cc1ccc2c(c1)C(=O)N(c1cccc(-c3ccc(C(N)=O)c4[nH]c5cc(OCC6COC(C)(C)O6)ccc5c34)c1C)C2
Solvent: CO
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)C(=O)N(c1cccc(-c3ccc(C(N)=O)c4[nH]c5cc(OCC(O)CO)ccc5c34)c1C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
A solution of racemic 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 44-4, 30 mg, 0.052 mmol) in methanol-DMSO was treated with TFA (0.5 mL) and the solution was stirred overnight at rt. The mixture was concentrated and purified by preparative HPLC to provide 7-(2,3-dihydroxypropoxy)-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as a white solid (9.4 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ 11.39 (1H, s), 8.16 (1H, br. s.), 7.94 (1H, d, J=7.7 Hz), 7.54-7.65 (3H, m), 7.49 (3H, t, J=7.9 Hz), 7.25-7.38 (2H, m), 6.99 (1H, d, J=7.7 Hz), 6.92 (1H, d, J=8.8 Hz), 6.60 (1H, d, J=1.3 Hz), 4.82-5.01 (3H, m), 4.60-4.71 (1H, m), 3.96-4.08 (1H, m), 3.76-3.96 (2H, m), 3.48 (2H, t, J=5.6 Hz), 2.44 (3H, s), 1.77-1.88 (3H, m). Mass spectrum m/z 536.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH:8]1[CH2:11][CH2:10][CH2:9]1.[C:13]([NH:21][NH2:22])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C(N(CC)CC)C>CC1C=CC(C)=CC=1>[Cl:1][C:2]1[C:7]([CH:8]2[CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]2[N:4]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:21][N:22]=2)[N:3]=1
Reactant: Clc1cc(C2CCC2)c(Cl)nn1
Reactant: NNC(=O)c1ccccc1
Agent: Cl
Solvent: Cc1ccc(C)cc1
Solvent: CCN(CC)CC
Product: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Yield: 34 %

Procedure:
A mixture of 3,6-dichloro-4-cyclobutylpyridazine from above (55.7 g, 0.27 mol), benzoic hydrazide (41.1 g, 0.30 mol) and triethylamine hydrochloride (41.5 g, 0.30 mol) in p-xylene (0.4 l) was stirred and heated at reflux under a stream of nitrogen for 24 hours. Upon cooling the volatiles were removed in vacuo. The residue was partitioned between dichloromethane and water. The aqueous was basified by the addition of solid potassium carbonate. Some dark insoluble material was removed by filtration at this stage. The aqueous phase was further extracted with dichloromethane (×2). The combined extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel eluting with 5%→10%→25% ethyl acetate/dichloromethane to give the title compound, (26.4 g, 34%) as an off-white solid. Data for the title compound: 1H NMR (360 MHz, CDCl3) δ 1.90–2.00 (1H, m), 2.12–2.28 (3H, m), 2.48–2.57 (2H, m), 3.69–3.78 (1H,m), 7.49–7.59 (3H, m), 7.97 (1H, s), 8.45–8.48 (2H, m); MS (ES+) m/e 285 [MH]+, 287 [MH]+.
Reaction SMILES: [NH2:1][C@H:2]([CH3:28])[CH2:3][N:4]1[C:8]2=[N:9][CH:10]=[N:11][C:12]([NH2:13])=[C:7]2[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][C:15]=2[F:27])=[N:5]1.[C:29]([CH2:31][C:32](O)=[O:33])#[N:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:13][C:12]1[N:11]=[CH:10][N:9]=[C:8]2[N:4]([CH2:3][C@H:2]([NH:1][C:32](=[O:33])[CH2:31][C:29]#[N:30])[CH3:28])[N:5]=[C:6]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:16][C:15]=3[F:27])[C:7]=12
Reactant: C[C@@H](N)Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)CC#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.6 %

Procedure:
To a solution of 1-[(2R)-2-aminopropyl]-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine (1826 .mg, 4.83 mmol), 2-cyanoacetic acid (821 mg, 9.7 mmol) and TEA (2.0 mL, 14.5 mmol) in DMF (25 mL) was added HATU (2.75 g, 7.24 mmol). The reaction mixture was stirred at room temperature for 20 hr. The mixture was then evaporated to an oil and dissolved in ethyl acetate (100 mL) and washed with 5% citric acid (50 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated. The crude material was purified by Isolera (10 g col, 2%-6% MeOH/DCM) to obtain 2.1 g (98%) of N-[(1R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-ethyl]-2-cyano-acetamide.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH2:14][C:15](=O)[CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]3[O:33][C:34]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[F:44])=[N:35][N:36]=3)=[O:31])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.N1C=CC=CC=1>C(Cl)Cl>[C:15]([CH2:16][C@H:17]1[CH2:18][CH2:19][C@H:20]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:30]([C:32]3[O:33][C:34]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[F:44])=[N:35][N:36]=3)=[O:31])=[CH:27][CH:28]=2)[CH2:21][CH2:22]1)#[N:14]
Reactant: NC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cc2)CC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CC[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cc2)CC1

Procedure:
Trifluoroacetic anhydride 0.042 mL, 0.05 mmol) was added to a stirred solution of N-{4-[trans-4-(2-amino-2-oxoethyl)cyclohexyl]phenyl}-5-[(2-fluorophenyl)amino]-1,3,4-oxadiazole-2-carboxamide (Example 516) (20 mg, 0.05 mmol) and pyridine (90 uL, 0.11 mmol) in DCM (2 mL). After 15 minutes DCM (10 mL) was added and the reaction mixture was washed sequentially with 1M HCl (5 mL), water (10 mL) and 10% ammonium hydroxide solution (5 mL) then dried and concentrated under reduced pressure to give the title compound (18 mg, 95%) as a solid; 1H NMR δ 1.13-1.30 (m, 3H), 1.40-1.54 (m, 2H), 1.60-1.75 (m, 1H), 1.76-1.92 (m, 5H), 2.40-2.50 (m, 1H), 7.10-7.19 (m, 1H), 7.20-7.35 (m, 4H), 7.68 (d, 2H), 8.03 (t, 1H), 10.75 (s, 1H), 10.93 (s, 1H); MS m/e MH+ 420.
Reaction SMILES: [O:1]([CH3:11])[CH:2]1[O:8][C@@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].[H-].[Na+].[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH2:17]Cl>CO>[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH2:17][O:4][C@H:3]1[C@H:5]([O:6][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]=2[Cl:14])[C@H:7]([CH2:9][O:10][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]=2[Cl:14])[O:8][CH:2]1[O:1][CH3:11]
Reactant: COC1O[C@@H](CO)[C@@H](O)[C@@H]1O
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC1O[C@@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@H]1OCc1ccc(Cl)cc1Cl
Reaction time: 0.67 h

Procedure:
Compound 1-1 from Step A is dissolved in anhydrous TBF and the solution is cooled in an ice bath. To the cold solution is added sodium hydride (60% dispersion in mineral oil) and the reaction mixture is stirred for 35 to 45 min under an argon atmosphere. To this mixture is added 2,4-dichlorobenzyl chloride slowly over 20 min. The reaction mixture is stirred for 72 h, then cooled in an ice bath. MeOH is added slowly to decompose excess NaH. The mixture is concentrated under reduced pressure and the residue is taken up in ethyl acetate and washed several times with water. The organic layer is dried over anhydrous Na2SO4, filtered, and evaporated. The residue is purified by silica gel chromatography using a mixture of hexane and ethyl acetate as the eluent. The appropriate fractions are combined and evaporated to afford compound 1-2.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@H:14]([C:16]([O:18]CC1C=CC=CC=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4](=[O:10])[O:5]C(C)(C)C.S(O)(C1C=[CH:44][C:42]([CH3:43])=[CH:41]C=1)(=O)=O.O.CN1CCOCC1.[NH:55]([C:73]([O:75][CH2:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)=[O:74])[C@H:56]([C:63]([O:65]N1C(=O)CCC1=O)=O)[CH2:57][O:58][C:59]([CH3:62])([CH3:61])[CH3:60].C(N(CC)CCN)C>[Pd].CN(C=O)C>[CH2:76]([O:75][C:73]([NH:55][C@H:56]([C:63]([NH:1][C@H:2]([C:11]([NH:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15])=[O:12])[CH:3]([C:42]([CH3:44])([CH3:43])[CH3:41])[C:4](=[O:10])[OH:5])=[O:65])[CH2:57][O:58][C:59]([CH3:60])([CH3:61])[CH3:62])=[O:74])[C:77]1[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=1
Reactant: C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Pd]
Agent: CCN(CC)CCN
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@@H](NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc1ccccc1)C(C(=O)O)C(C)(C)C)C(=O)O
Reaction time: 18 h

Procedure:
Z-Asp(OtBu)-Ala-OBzl (43,6 g, 90 mmol) was dissolved 1 liter DMF and hydrogenated in the presence of Tos-OH.H2O (17,1 g, 90 mmol) and 10% Pd-C. After the hydrogenation was completed the catalyst was filtered off. The filtrate was cooled to 0°, neutralized with N-methylmorpholine (9,9 ml, 90 mmol) and added to Z-Ser(tBu)-OSu. Another portion of N-methylmorpholine (9,9 ml, 90 mmol) was added and the reaction mixture was stirred at 0° for 1 h and at 25° for 18 h. 2-Diethylamino-ethylamine (2,83 ml, 20 mmol) was added to the reaction mixture and stirring was continued for 4 h. The solution was evaporated in vacuo, the residue dissolved in 0,5N NaOH (0,5 l) and extracted with ether (3×0,2 l). To the alkaline phase 0,4 l ethyl acetate was added and acidified with 5% KHSO4 /10% K2SO4 -solution. The acidic layer was again extracted with ethyl acetate (2×0,3 l). The combined organic layers were washed with 5% KHSO4 /10% K2SO4 -sol. (1×0,3 l) and saturated NaCl-sol., dried over Na2SO4, filtered and evaporated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][CH:13]([CH3:25])[CH2:14][CH:15]([C:18]1[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[CH2:16][NH2:17]>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH:15]([C:18]1[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[CH2:14][CH:13]([CH3:25])[CH3:12])=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ccc(C(CN)CC(C)C)cn1
Product: Cc1ccc(C(CNC(=O)c2cccc(Cl)c2Cl)CC(C)C)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 4-methyl-2-(6-methylpyridin-3-yl)-pentylamine. LCMS (MH+): m/z=364.9, tR (minutes, Method A)=1.43
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17]C)=O)[C:5]([CH2:11]Cl)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:24]([CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[C:15](=[O:17])[C@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:13][C:4]=2[CH:3]=1
Reactant: NCc1ccncc1
Reactant: COC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1CCl)C(=O)OC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
(S)-Dimethyl 2-((7-chloro-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (120 mg, 0.33 mmol) was dissolved in DMF (1.0 mL). 4-Aminomethylpyridine (100 μL, 1.0 mmol) was added to the mixture. Reaction stirred at room temperature for 24 hours. Mixture was diluted with ethyl acetate. Mixture was washed twice with water and once with brine. Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Residue was dissolved in toluene (4 mL). Acetic acid (1 mL) was added to the mixture. Reaction was heated at reflux for 3.5 hours. Mixture was cooled to room temperature then diluted with ethyl acetate. Material was washed once with water and twice with aqueous sodium bicarbonate. Aqueous was made basic with sodium bicarbonate. Back extracted from the aqueous twice with ethyl acetate. Combined organics were dried (magnesium sulfate), filtered and concentrated in vacuo. Residue was purified with silica gel chromatography eluting dichloromethane and 2N ammonia in methanol. Title compound was obtained as yellow solid in 48% yield. MS m/e (M+H)+=399.2.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:20]([OH:30])[CH2:21][C@@H:22]([CH:27]([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.Cl.[CH2:39]([C@H:46]([CH2:50][C:51]([N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)=[O:52])C(O)=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[CH2:39]([C@H:46]([CH2:50][C:51]([N:53]1[CH2:54][CH2:55][O:56][CH2:57][CH2:58]1)=[O:52])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:20]([OH:30])[CH2:21][C@@H:22]([CH:27]([CH3:28])[CH3:29])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:5])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)C
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
A mixture of 300 mg (0.56 mmole) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-isopropyl-N-methylhexanamide [prepared as described in Example 1(a)] and 5 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. The solvent was then removed by distillation under reduced pressure. Diethyl ether was added to the residue, and the mixture was concentrated by evaporation under reduced pressure. This operation was repeated three times. After the final residue had been dried under reduced pressure for 8 hours, the dried material was suspended in 10 ml of anhydrous tetrahydrofuran. 170 mg (0.61 mmole) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid were then added to the suspension. 0.09 ml (0.59 mmole) of 95% diethyl cyanophosphonate and 0.26 ml (1.86 mmole) of triethylamine were then added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred at room temperature for 8 hours, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by preparative thin layer chromatography on silica gel (using a 10:1 by volume mixture of methylene chloride and methanol as the developing solvent), to afford 281 mg (yield 72%) of the title compound as white crystals, melting at 83°-86° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:12][C:11]2=[O:23])=[CH:6][CH:5]=1.ClCCl.[I:29]Cl>O>[F:25][C:2]([F:1])([F:24])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:15](=[O:16])[C:14]([I:29])=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:12][C:11]2=[O:23])=[CH:8][CH:9]=1
Reactant: O=c1cc(-c2ccccn2)[nH]c(=O)n1-c1ccc(OC(F)(F)F)cc1
Reactant: ClI
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccccn2)c(I)c(=O)n1-c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 44.1 %

Procedure:
1.0 g of the obtained 3-(4-trifluoromethoxyphenyl)-6-(2-pyridyl)-2,4(1H,3H)-pyrimidinedione was added to 20 ml of dichloromethane, and 0.7 g of iodine monochloride was added thereto with stirring at room temperature. The resulting solution was further stirred at room temperature for 3 hours, then poured into 100 ml of water and extracted with 100 ml of ethyl acetate. The obtained organic layer was washed with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then the solvent was distilled away under reduced pressure to obtain 0.60 g of the objective compound.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:29]([S:26]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH2:10][CH2:11]2)(=[O:28])=[O:27])=[CH:30][CH:31]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3cccc(Oc4ccccc4)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3cccc(Oc4ccccc4)c3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylic ethyl ester (10.7 g, 24 mmol) dissolved in THF:Methanol (75: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 5.0 g (76%); off white solid; MS: 524.3 (M+H)+
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Br.[Br:13][CH2:14][CH2:15][NH2:16]>O1CCOCC1.[OH-].[Na+].O1CCOCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:16][CH2:15][CH2:14][Br:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCCBr
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NCCBr)OCc1ccccc1
Yield: 92 %

Procedure:
A solution of CBz-Cl (7.7 mL; 54 mmol) in dioxane (5 mL) was added to a cold (0° C.) stirred solution of 2-bromoethylamine hydrobromide (10.0 g; 49 mmol) in 40 mL 1M NaOH:dioxane (3:1) under Schotten-Bauman conditions. The reaction mixture was allowed to attain rt. and extracted with CHCl3. The organic layer was separated, concentrated and purified by column chromatography (CHCl3) to give the sub-title compound in a 92% yield.