Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@@H:27]([C:32](O)=[O:33])[C@@H:28]([CH2:30][CH3:31])[CH3:29])=[O:25])[CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](=[O:16])[OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([C@H:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:36].O.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH2:35]([C@H:37]([NH:44][C:32](=[O:33])[C@@H:27]([C@@H:28]([CH2:30][CH3:31])[CH3:29])[NH:26][C:24](=[O:25])[C@H:12]([CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:36]
Reactant: CC[C@@H](C)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)C(=O)O
Reactant: CC[C@H](N)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC[C@H](NC(=O)[C@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)[C@H](C)CC)c1ccccc1
Reaction time: 1 h
Yield: 33.1 %

Procedure:
To a solution of 6.69 g (14.2 mmols) of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-isoleucine and 2.04 g (15.1 mmols) of (S)-α-ethylbenzylamine in 200 ml of methylene chloride were added 2.73 g (14.2 mmols) of water-soluble carbodiimide hydrochloride and 1.92 g (14.2 mmols) of HOBt under cooling and stirred for one hour under cooling and then overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and 150 ml of ethyl acetate was added. The resulting residue was washed two times each with 70 ml of aqueous 5% citric acid, once with 70 ml of water, two times each with 70 ml of aqueous 5% sodium hydrogencarbonate and once with 70 ml of brine in that order. The resulting organic layer was dried with anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The resulting residue was dissolved in chloroform and concentrated under reduced pressure. The resulting solid residue was washed with ethyl acetate and dried to obtain 2.81 g (4.7 mmols) of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-isoleucine (S)-α-ethylbenzylamide.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.C(N)(C)C>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Solvent: CC(C)N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 169.9 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (8 ml) is added to the bottle, and isopropylamine (7.7 ml) is added thereto under refluxing within 15 min. The above mixture is further reacted at the temperature for 0.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (10.8 g). The yield is about 70.0%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:23])[CH:3]=1.[CH3:24][C@@H:25]1[CH2:29][O:28][C:27](=[O:30])[NH:26]1>>[F:23][C:4]1[CH:3]=[C:2]([N:26]2[C@H:25]([CH3:24])[CH2:29][O:28][C:27]2=[O:30])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3F)CC2)nc1
Yield: 94.7 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2-fluorophenyl)[4-(5-methylpyridin-2-yl)piperazin-1-yl]methanone (378 mg) described in Preparation Example 184 and (R)-4-methyloxazolidin-2-one (171 mg) described in Preparation Example 25, the title compound (377 mg) was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:59][CH3:60])=[C:10]([CH2:19][NH:20][C:21](=[O:58])[C:22]([CH3:57])([CH3:56])[CH2:23][C:24]([NH:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:55])=[C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][N:41]5[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[C@@H:43]([CH3:54])[CH2:42]5)[CH:35]=4)[CH:33]=3)=[O:25])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl>O1CCOCC1.CO>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:59][CH3:60])=[C:10]([CH2:19][NH:20][C:21](=[O:58])[C:22]([CH3:57])([CH3:56])[CH2:23][C:24]([NH:26][CH2:27][C:28]3[CH:33]=[C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][N:41]5[CH2:46][CH2:45][NH:44][C@@H:43]([CH3:54])[CH2:42]5)[CH:35]=4)[C:31]([F:55])=[CH:30][CH:29]=3)=[O:25])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C(C)(C)CC(=O)NCc1ccc(F)c(-c2cccc(CN3CCN(C(=O)OC(C)(C)C)[C@@H](C)C3)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C(C)(C)CC(=O)NCc1ccc(F)c(-c2cccc(CN3CCN[C@@H](C)C3)c2)c1
Temperature: 60 °C
Yield: 3.5 %

Procedure:
174(d) 1,1-Dimethylethyl (2S)-4-{[5′-({[4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3,3-dimethyl-4-oxobutanoyl]amino}methyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate was dissolved in 2 mL of dioxane and 0.5 mL of MeOH. HCl (concentrated, 101 mg, 2.78 mmol) was added to the resultant solution and heated at 60° C. for 1 h. The solution was applied to an amine column, rinsed with 4 mL of MeOH to afford 7 mg of the title compound (3.5%). LC-MS m/z 727 (M+H)+, 1.23 min (ret time). The structure of the title compound was confirmed by gCOSY45, gHMQC, gHMBC and 13C gaspe spectra.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([Cl:24])=[O:23])([O-:19])=[O:18]>>[ClH:24].[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[N+:17]([O-:19])=[O:18])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1
Product: Cl
Product: O=C(Nc1ccc(N2CCN3CCC2CC3)cc1)c1ccccc1[N+](=O)[O-]

Procedure:
Was prepared by Method G from 4-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)phenylamine and 2-nitrobenzoyl chloride. Mp. >280° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([NH2:20])[CH2:8][C@@H:7]1[CH3:21])=[O:5])[CH3:2].[F:22][C:23]([F:39])([F:38])[C:24]1[CH:25]=[C:26]([CH2:34][C:35](O)=[O:36])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.CN(C)CCCN=C=NCC>ClCCl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([NH:20][C:35](=[O:36])[CH2:34][C:26]2[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:24]([C:23]([F:38])([F:22])[F:39])[CH:25]=2)[CH2:8][C@@H:7]1[CH3:21])=[O:5])[CH3:2]
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](N)C[C@@H]1C
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](NC(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cis-4-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (150 mg, 0.50 mmol) and 3,5-bis-trifluoromethylphenylacetic acid (138 mg, 0.51 mmol) in 1.5 ml anhydrous dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (192 mg, 0.66 mmol) and the resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with 50 ml ethyl acetate and was washed with 0.1N HCl (2×10 mL), 0.1N NaOH (2×10 mL) and brine (1×10 mL). The organic phase was dried (MgSO4), filtered and concentrated, and the the residue was chromatographed using 20:1 hexanes:ethyl acetate. The title compound crystallized out of the combined fractions (129 mg, 46%). Me 157-9° C.; MS m/z 549 (M+ +1); 1H NMR (CDCl3) δ 1.07 (d, 3H), 7.70-7.78 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]1[CH2:8][CH:7]([S:9][C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)[CH2:6][N:5]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[CH:25]1[C:33]2[C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[O:30][C:29]=2[C:28]([C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]1[CH2:8][CH:7]([S:9][C:10]2[CH:15]=[CH:14][C:13]([C:41]3[CH:42]=[CH:43][C:38]([C:28]4[C:29]5[O:30][C:31]6[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=6[C:33]=5[CH:25]=[CH:26][CH:27]=4)=[CH:39][CH:40]=3)=[CH:12][CH:11]=2)[CH2:6][N:5]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: OB(O)c1ccc(-c2cccc3c2oc2ccccc23)cc1
Reactant: COC(=O)[C@@H]1CC(Sc2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
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: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CC(Sc2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 70.7 %

Procedure:
A solution of 4-(4′-bromophenylsulfanyl)-N-tert-butoxycarbonyl-proline methyl ester (416 mg, 1 mmol), (4-Dibenzofuran-4-yl-phenyl)boronic acid (302 mg, 1.05 mmol), Pd(PPh3)4 (52 mg, 5% mol) in toluene (10 mL) and ethanol (2.5 mL) was heated until the solution became clear and subsequently treated with 2 M K2CO3 (1.5 mL). The reaction mixture was heated to reflux for 2 h, cooled to room temperature, diluted with ethyl acetate (100 mL). The organic layer was washed successively with 2% aq HCl and sat. aq NaCl, dried over MgSO4 and concentrated. Purification by flash column chromatography (2-10% ethyl acetate in heptane) to give 4-(4′-dibenzofuran-4-yl-bipheny-4-ylsulfanyl)-N-tert-butoxycarbonyl-proline methyl ester (410 mg, 73%). 1H NMR (CDCl3), δ 8.01 (m, 3H), 7.95 (d, J=6 Hz, 1H), 7.73 (d, J=7 Hz, 2H), 7.62 (m, 4H), 7.41 (m 5H), 4.37-4.28 (m, 1H), 4.01 (m, 1H), 3.76 (s, 3H), 3.69 (m, 1H), 3.42 (m, 1H), 2.67 (m, 1H), 2.07 (m, 1H), 1.44 (s, 9H). LCMS 580 (M++1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.CS(OS(C)(=O)=O)(=O)=O.CCN(C(C)C)C(C)C.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][N:40]1[CH2:39][CH2:38][N:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[F:30])[CH2:42][CH2:41]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: OCc1cc2ccccc2s1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccccc1N1CCN(Cc2cc3ccccc3s2)CC1

Procedure:
The product from Example 8A (150 mg 0.9 mmol), methane sulfonic anhydride (159 mg, 0.9 mmol), and DIEA (475 μL 2.7 mmol) were combined. After stirring, 1-(2-fluorophenyl)piperazine (181 mg, 1.0 mmol) was also combined and processed as described in Example 8B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.63 (m, 4H) 3.04 (m, 4H) 3.86 (s, 2H) 7.04 (m, 6H) 7.32 (m, 2H) 7.77 (m, 1H). (ESI) m/z 327 (M+H)+.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][NH2:5].[CH3:6]CN(C(C)C)C(C)C.C(Cl)(Cl)=S.[Br:19][C:20]1[CH:21]=[C:22]([NH2:27])[C:23]([NH2:26])=[CH:24][CH:25]=1>[Hg]=O.C1COCC1.C(Cl)Cl>[Br:19][C:20]1[CH:25]=[CH:24][C:23]2[NH:26][C:6]([NH:5][CH2:4][CH2:3][F:2])=[N:27][C:22]=2[CH:21]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: NCCF
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: O=[Hg]
Agent: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: FCCNc1nc2cc(Br)ccc2[nH]1
Temperature: 0 °C
Reaction time: 12 h
Yield: 54 %

Procedure:
2-Fluoroethylamine hydrochloride salt (282.4 mg, 2.83 mmol) was suspended in 1:1 THF:DCM (6 mL) followed by addition of DIPEA (2.5 mL, 14.35 mmol). The mixture was cooled to 0° C. followed by slow addition of thiophosgene (217 uL, 2.8 mmol) by syringe over five minutes then allowed to slowly warm to room temperature over 30 minutes. 4-Bromobenzene-1,2-diamine (530 mg, 2.8 mmol) was then added and the reaction mixture was allowed to stir at room temperature over an additional 12 h. The mixture was concentrated and the residue partitioned with ethyl acetate and 10% aqueous citric acid. The organic phase was washed twice with additional 10% aqueous citric acid then brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude mixture of thiourea thus obtained was taken into THF (15 mL) followed by addition of mercury (II) oxide (640 mg, 2.95 mmol). The mixture was brought to reflux for 6 h then stirred an additional 60 h at room temperature. The crude mixture was filtered through a bed of celite with ethyl acetate washing and the filtrate concentrated then taken back into ethyl acetate. The organic solution was washed once with 1 M aqueous hydrochloric acid and the organic phase discarded. The aqueous phase was filtered to remove trace insoluble residue and the filtrate basified to pH 9-10 by dropwise addition of 50% aqueous sodium hydroxide. The aqueous phase was then extracted once with ethyl acetate and the organic solution was washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated to afford crude 5-bromo-N-(2-fluoroethyl)-1H-benzo[d]imidazol-2-amine (390 mg, 53% yield) which was carried forward without further purification. MS (EI) for C9H9BrFN3: 258, 260 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([OH:28])=O)=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]([CH3:39])[C:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([N:36]2[CH2:35][CH2:34][N:33]([C:31](=[O:32])[N:30]([CH3:29])[CH3:39])[CH2:38][CH2:37]2)=[O:28])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: CN(C)C(=O)N1CCNCC1
Product: CN(C)C(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCCN(C(=O)OC(C)(C)C)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 47a), from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylic acid and piperazine-1-carboxylic acid dimethyl amide. White solid. MS (m/z): 527.3 (M+H)+.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:38])[C@H:11]([N:14]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]2[O:35][CH2:36][O:37][C:31]=2[CH:30]=1)[S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[CH:20][C:19]=1[CH3:27])(=[O:17])=[O:16])[CH2:12][OH:13])C1C=CC=CC=1>[Pd].C(O)C.O1CCCC1>[OH:8][NH:9][C:10](=[O:38])[C@H:11]([N:14]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]2[O:35][CH2:36][O:37][C:31]=2[CH:30]=1)[S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[CH:20][C:19]=1[CH3:27])(=[O:17])=[O:16])[CH2:12][OH:13]
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CO)C(=O)NOCc2ccccc2)c(C)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CO)C(=O)NO)c(C)c1
Reaction time: 0.75 h
Yield: 97.6 %

Procedure:
To a solution of N-benzyloxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-hydroxypropionamide (3.0 g, 5.39 mmol) in argon deoxygenated 80% ethanol-tetrahydrofuran (160 mL) was added 10% Pd—C (1.3 g), and the resulting mixture was hydrogenated at atmospheric pressure for 45 min. The reaction mixture was degassed under argon and the slurry was filtered over Celite. The Celite cake was washed with ample 80% ethanol-methylene crystallize. The slurry was filtered, washing with 50% diethyl ether-hexanes to afford N-hydroxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-hydroxypropionamide (2.38 g) as a white solid.
Reaction SMILES: Cl.C1(S(Cl)(=O)=O)C2C(=CC=CC=2)C=CN=1.[CH:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([S:26]([N:29]3[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]3)(=[O:28])=[O:27])[C:20]=2[CH:19]=[CH:18][N:17]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O>ClCCl>[CH:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([S:26]([N:29]3[CH2:33][CH2:32][C:31](=[O:34])[CH2:30]3)(=[O:27])=[O:28])[C:20]=2[CH:19]=[CH:18][N:17]=1
Reactant: O=S(=O)(c1cccc2cnccc12)N1CCC(O)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)(Cl)c1nccc2ccccc12
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CCN(S(=O)(=O)c2cccc3cnccc23)C1

Procedure:
Substantially the same procedures as in Example 1 were repeated except that 2.64 g of 1-isoquinolinesulfonyl chloride hydrochloride was used in place of 6.0 g of 1-chloro-5-isoquinolinesulfonyl chloride hydrochloride and that 2.22 g of the thus obtained 1-(5-isoquinolinesulfonyl)-3-hydroxypyrrolidine was reacted in dichloromethane with 1.08 g of oxalyl chloride and 0.67 g of dimethylsulfoxide. There was obtained 1-(5-isoquinolinesulfonyl)-3-pyrrolidone.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])(C)(C)C.CCCCC.[B:23](OC)([O:26]C)[O:24]C>CCOCC.O1CCCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([B:23]([OH:26])[OH:24])[CH:3]=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: CC1(C)COc2ccc(Br)cc21
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)COc2ccc(B(O)O)cc21
Reaction time: 1 h
Yield: 47.9 %

Procedure:
A stirred, cooled (−78° C.) solution of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (Intermediate 2, 1.44 g, 6.2 mmol) in 18 mL of anhydrous ether and 5 mL of anhydrous tetrahydrofuran under argon, was treated with a 1.7M solution of t-butyllithium in n-pentane (7.65 mL, 13.02 mmol) and the resulting solution was stirred at the same temperature for 1 h. Trimethyl borate (1.6 mL, 13.02 mmol) was added and the reaction mixture was allowed warm from −78° C. to −30° C. over 2 h. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ether. The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to a foamy solid. Flash column chromatography using 25-100% ethyl acetate in hexane as the eluent afforded 0.57 g, 47.8% of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:31]=[CH:30][C:19]([CH2:20][CH:21]([C:26]([O:28]C)=O)[C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1.[CH3:32][NH2:33]>CO.O1CCCC1>[CH3:32][NH:33][C:26]([CH:21]([CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:31][CH:30]=1)[C:22]([O:24][CH3:25])=[O:23])=[O:28]
Reactant: CN
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Dimethyl 2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]malonate (3.00 g, 7.08 mmol) synthesized according to the method described in WO95/18125 was dissolved in methanol-tetrahydrofuran (1:1, 100 ml), and 40% aqueous methylamine solution (50 ml) was added. The mixture was stirred at room temperature for 0.5 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=1:2) to give the title compound (1.50 g, yield 50%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
To a solution of 3-Methyl-piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 5.3 mmol) and of 1-Bromo-4-trifluoromethyl-benzene (1.0 g, 4.4 mmol) in toluene (10 ml) were added sodium-tert butylate (0.6 g, 6.2 mmol), 2-(dicyclohexylphosphino)biphenyl (31. mg,89 mmol), and tris(dibenzylideneacetone)dipalladium-chloroform complex (23 mg, 22 mmol). The reaction mixture was then stirred for 16 hours at 80° C. After allowing to cool to room temperature the reaction mixture was concentrated in vacuo and purified by column chromatography (SiO2, 70 g, heptane/ethyl acetate 0-30%) to give the title compound as a light brown solid (0.47 g); MS (m/e): 345.2 (M+H+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(#N)C.ClCCl>[F:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:13](=[O:15])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=c1[nH]c2ccc(F)cc2c(=O)o1
Temperature: 55 °C

Procedure:
To a solution of 2-amino-5-fluorobenzoic acid (1.00 g, 6.40 mmol) in acetonitrile (8 mL) was added a solution of triphosgene (0.64 g, 2.1 mmol) in dichloromethane (5 mL) and pyridine (1.1 mL, 13.0 mmol) simultaneously within 5 min. The resulting pale yellow suspension was heated at 55° C. for 2 hours. The solvents were evaporated under vacuum, and the residue was stirred with water (5 mL). The precipitate obtained was filtered and dried to afford 6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione. Yield: 1.06 g (91%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Br:18])[C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>>[CH2:1]([N:8]([CH2:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[CH:16][C:17]=1[Br:18])[C:22]([CH:19]1[CH2:21][CH2:20]1)=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Br)c(CNCc2ccccc2)c1
Reactant: O=C(Cl)C1CC1
Product: N#Cc1ccc(Br)c(CN(Cc2ccccc2)C(=O)C2CC2)c1

Procedure:
3-(Benzylamino-methyl)-4-bromo-benzonitrile and cyclopropanecarbonyl chloride were reacted as described in Example 2, Step 3 to provide cyclopropanecarboxylic acid benzyl-(2-bromo-5-cyano-benzyl)-amide.