Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12]([CH3:18])(OCOC)[C:11]([CH2:19][CH:20]=[CH2:21])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([SiH](CC)CC)C.[Cl-].[Cl-].C([Al+2])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCC.ClCCl>[Si:1]([O:8][CH:9]1[CH2:13][C:12]([CH3:18])=[C:11]([CH2:19][CH:20]=[CH2:21])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1(C)OCOC
Agent: CC[Al+2]
Agent: CC[SiH](CC)CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCCCCC
Product: C=CCC1=C(C)CC(O[Si](C)(C)C(C)(C)C)C1
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To a solution mixture of 4.5 g of (1RS,4RS)-3-allyl-4-methyl-4-methoxymethoxy-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether and 50 ml of dichloromethane was added under nitrogen stream 3 ml of triethylsilane by drops at -78° C., and the resulting mixture was stirred for 15 minutes. Thereafter, under the same conditions, 17.5 ml of 0.93 M hexane solution of ethylaluminum dichloride was added by drops and the resulting mixture was brought up to -10° C. over 1 hour. Then the reaction liquid was poured into ice-cooled 5% aqueous solution of citric acid and extracted with diethyl ether. The ether layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography to obtain 2 g of (RS)-3-allyl-4-methyl-3-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 55%
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:93]=[CH:94][CH:95]=1)[CH2:50][N:51]1[C:55]([CH3:56])=[C:54]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:71]=[CH:70][C:69]([N:72]5[CH2:77][CH2:76][N:75]([CH2:78][C@@H:79]([OH:81])[CH3:80])[CH2:74][CH2:73]5)=[CH:68][CH:67]=4)[CH:64]=3)[N:59](S(C3C=CC(C)=CC=3)(=O)=O)[CH:58]=2)[C:53]([CH3:92])=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:93]=[CH:94][CH:95]=1)[CH2:50][N:51]1[C:55]([CH3:56])=[C:54]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:67]=[CH:68][C:69]([N:72]5[CH2:77][CH2:76][N:75]([CH2:78][C@@H:79]([OH:81])[CH3:80])[CH2:74][CH2:73]5)=[CH:70][CH:71]=4)[CH:64]=3)[NH:59][CH:58]=2)[C:53]([CH3:92])=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCN(C[C@H](C)O)CC4)cc3)cc12
Yield: 24.2 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (2S)-1-(4-(4-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)propan-2-ol (165 mg, 0.238 mmol) was hydrolyzed with lithium hydroxide (100 mg, 2.38 mmol) in THF/methanol/water (20/10/5 mL) to yield 31 mg (13% yield) of desired product. 1H NMR (CD3OD, 300 MHz): δ 8.43-8.42 (d, 1H), 7.838-7.831 (d, 1H), 7.50-7.57 (d, 2H), 7.40-7.30 (m, 2H), 7.05-6.95 (m, 4H), 6.95-6.84 (m, 1H), 5.35 (s, 2H), 4.05-3.95 (m, 1H), 3.25-3.22 (t, 4H), 2.80-2.62 (m, 4H), 2.50-2.30 (m, 2H), 2.20 (s, 3H), 2.16 (s, 3H), 1.17-1.15 (d, 3H). MS: m/z=538.9 (M+1), HPLC: 95.51% in method A.
Reaction SMILES: CO[C:3](=[O:29])[C@H:4]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:5][C:6]1[C:7]([CH2:16]Cl)=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2.[F:30][C:31]([F:35])([F:34])[CH2:32][NH2:33].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:22]([O:21][C:19](=[O:20])[NH:18][C@H:4]1[C:3](=[O:29])[N:33]([CH2:32][C:31]([F:35])([F:34])[F:30])[CH2:16][C:7]2[C:8]3[CH:9]=[N:10][NH:11][C:12]=3[C:13]([Cl:15])=[CH:14][C:6]=2[CH2:5]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CCl)NC(=O)OCc1ccccc1
Reactant: NCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)OCc1ccccc1
Temperature: 40 °C

Procedure:
A mixture of 2-(R)-benzyloxycarbonylamino-3-(7-chloro-4-chloromethyl-1H-indazol-5-yl)propionic acid methyl ester (525 mg, 1.20 mmol) [Chaturvedula et al. WO 2006/052378], trifluoroethylamine (1.0 g, 10.2 mmol), and K2CO3 (499 mg, 3.61 mmol) in CH3CN (15 mL) was heated at 40° C. in a sealed vessel for 45 h. Additional trifluoroethylamine (1.0 g, 10.2 mmol) was added and the mixture was heated at 40° C. for a further 48 h and then allowed to cool to ambient temperature. The reaction mixture was filtered through a 0.45 μm PTFE membrane and the filtrate was concentrated in vacuo. The residue was dissolved in toluene (10 mL) and AcOH (1 mL) and the mixture was heated at reflux for 6 h, allowed to cool to ambient temperature, and partitioned between saturated aqueous NaHCO3 (30 mL) and EtOAc (60 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc-100:0 to 50:50, to provide the title compound. MS: m/z=467.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([C:18](=[O:33])[NH:19][C:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([O:30][CH3:31])[CH:22]=1)[NH:10]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18](=[O:33])[NH:19][C:20]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([O:30][CH3:31])[CH:22]=2)=[N:10]1
Reactant: COc1cc(C(=O)NC(=O)N(NC(=O)OC(C)(C)C)c2c(Cl)cccc2Cl)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26.2 %

Procedure:
To a solution of tert-butyl 2-(2,6-dichlorophenyl)-2-((3-methoxy-4-nitrobenzoyl) carbamoyl)hydrazinecarboxylate (1.0 g, 2.002 mmol) in DCM (20 mL) was added trifluoro acetic acid (2.0 mL). The reaction mass was stirred at RT for 2-3 h. Excess of solvent was removed at low temperature. The reaction mass was quenched in ice and filter off to afford 0.200 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.98 (s, 3H), 7.56-7.62 (m, 2H), 7.69-7.75 (m, 3H), 8.02 (d, J=8.4 Hz, 1H), 11-12 (br s, 1H); MS (m/z): 382.07 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[N:32]1([CH2:37][CH2:38][C@H:39]2[CH2:44][CH2:43][C@H:42]([NH2:45])[CH2:41][CH2:40]2)[CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:45][C@H:42]3[CH2:43][CH2:44][C@H:39]([CH2:38][CH2:37][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH2:40][CH2:41]3)=[O:29])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N[C@H]1CC[C@H](CCN2CCCC2)CC1
Reactant: O=C(O)CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C(CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1)N[C@H]1CC[C@H](CCN2CCCC2)CC1

Procedure:
The title compound was prepared from [5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid (Example 2c) and trans-4-(2-pyrrolidin-1-yl-ethyl)-cyclohexylamine dihydrochloride (Reference Example 4) according to the method described in Example 1e. MS (EI) 627.2 (MH+).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)(=[O:5])=[O:4]>CO.CCOC(C)=O.[Pd]>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cccc(N)c1

Procedure:
A solution of N-methyl-3-nitrobenzene sulfonamide (608 mg, 2.8 mmole) in 30 mL of MeOH and 5 mL of EtOAc was treated with 10% Pd/C (100 mg) and hydrogenated at 1 atmosphere H2 pressure for 16 hours. The catalyst was filtered, and the filtrate evaporated. The residue was dissolved in EtOAc, washed with H2O, dried and the solvent removed, and gave the titled product, 498 mg (96%). MS (ESI) 187 (MH+).
Reaction SMILES: Br[CH:2]([CH3:9])[C:3](=O)[C:4]([O:6][CH3:7])=[O:5].[CH3:10][CH:11]([CH3:15])[C:12](=[S:14])[NH2:13]>C1COCC1>[CH:11]([C:12]1[S:14][C:2]([CH3:9])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[N:13]=1)([CH3:15])[CH3:10]
Reactant: COC(=O)C(=O)C(C)Br
Reactant: CC(C)C(N)=S
Solvent: C1CCOC1
Product: COC(=O)c1nc(C(C)C)sc1C

Procedure:
A mixture of methyl 3-bromo-2-oxobutanoate (4.6 g) and 2-methylpropanethioamide (2.5 g) in THF (100 mL) was heated at reflux for 18 hours. The solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution and the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified by flash silica chromatography using 17% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.7 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.F[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:1][C:2]2[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)c1ccc(Oc2cccc(C(C)=O)c2)cc1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(3-hydroxyphenyl)ethanone (8 g, 58.7 mmol), 1-(4-fluorophenyl)ethanone (8.1 g, 58.7 mmol) and anhydrous potassium carbonate (16.2 g, 117.5 mmol) in DMSO (150 mL) was stirred for 16 hours at 140° C. The mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 1M HCl until pH=6-7 and extracted with ethyl acetate. The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was chromatographed on silica gel (ethyl actetate/heptane: 1/1) resulting in 1-(3-(4-acetylphenoxy)phenyl)ethanone (11 g, 74%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:10]=[C:9]([C:20](OC)=[O:21])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[BH4-]>C1COCC1>[C:1]1([C:7]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])[N:10]=[C:9]([CH2:20][OH:21])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(-c2ccccc2)n(COCC[Si](C)(C)C)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(CO)cc1-c1ccccc1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of methyl 5-phenyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylate (380 mg, 1.143 mmole) in THF (5 mL) was added 2M LiBH4 in THF (0.9 mL, 1.800 mmole) at RT. After 30 min the mixture was heated to reflux. After 45 min the mixture was cooled to RT and quenched by slow addition of 1M NaOH. The mixture was diluted with H2O and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered through a pad of Celite washing with CH2Cl2, and concentrated to give the title compound (327 mg, 94%) as a clear oil. 1H NMR (399 MHz, CDCl3): δ 7.60 (dd, J=7.4, 1.5 Hz, 2 H); 7.48-7.40 (m, 3 H); 6.40 (s, 1 H); 5.38 (s, 2 H); 4.74 (d, J=5.8 Hz, 2 H); 3.76-3.67 (m, 2 H); 2.03-1.96 (m, 1 H); 0.98-0.89 (m, 2 H); 0.01 (s, 9 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:18]([OH:20])=O)=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[CH3:55][C:56]([O:59][C:60]([NH:62][CH2:63][C@H:64]([NH2:69])[C:65]([O:67][CH3:68])=[O:66])=[O:61])([CH3:58])[CH3:57].Cl.C(N(CC)CC)C>CN(C=O)C>[CH3:68][O:67][C:65](=[O:66])[C@@H:64]([NH:69][C:18]([C:11]1[S:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:13][C:12]=1[C:14]([F:15])([F:16])[F:17])=[O:20])[CH2:63][NH:62][C:60]([O:59][C:56]([CH3:55])([CH3:58])[CH3:57])=[O:61]
Reactant: CC(C)(C)OC(=O)Nc1nc(C(F)(F)F)c(C(=O)O)s1
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(NC(=O)OC(C)(C)C)nc1C(F)(F)F
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of 2-tert-Butoxycarbonylamino-4-trifluoromethyl-thiazole-5-carboxylic acid (6.23 g, 19.96) in anhydrous DMF (100 mL) was added HBTU (8.29 g, 24.97 mmol), HOBt (3.39 g, 19.96 mmol), H-DAP(BOC)-OME HCL (8.08 g, 31.02 mmol) and triethylamine (11.97 mL, 85.94 mmol). The reaction mixture was stirred at 25′C for 1 h and concentrated under reduced pressure to remove most of the DMF. The residue was diluted with ethyl acetate (200 mL), washed with 1:1 water/brine (40 mL), aqueous 1N HCl (40 mL), brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography (40% to 100% EtOAc in hexanes) to give (S)-3-tert-Butoxycarbonylamino-2-[(2-tert-butoxycarbonylamino-4-trifluoromethyl-thiazole-5-carbonyl)-amino]-propionic acid methyl ester (8 g, 78%) as a pale yellow foam. MS m/e 513.5 (M+H+).
Reaction SMILES: OC1C=CC(O[CH2:7][C:8]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:9])=CC=1.C(C(O)=O)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:7][C:8]([O:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: O=C(COc1ccc(O)cc1)OCCc1ccc(O)cc1
Product: O=C(CCc1ccc(O)cc1)OCCc1ccc(O)cc1

Procedure:
Using a similar procedure, 4-hydroxyphenethyl 2-(4-hydroxyphenoxy)acetate (compound of Formula (V) where L1=bond, L4=—O—, m=2, n=1, y1=y2=0) is prepared by substituting 2-(4-hydroxyphenoxy)acetic acid for desaminotyrosine. Similar results are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].[Cl:12][C:13]1[C:18]2[O:19][C:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][C:21]=3[C:17]=2[CH:16]=[C:15](Br)[CH:14]=1>>[Cl:12][C:13]1[C:18]2[O:19][C:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][C:21]=3[C:17]=2[CH:16]=[C:15]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Br)cc3c2C1
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccc(Cl)cc4)cc3c2C1
Yield: 48 %

Procedure:
Sodium 4-chlorobenzenesulfinate was coupled with the product of Example 44, step B following the procedure of Example 29, step C. The crude product was purified by flash column chromatography (SiO2, 3:2 hexanes/ethyl acetate) to give tert-butyl 6-chloro-8-(4-chlorophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (120 mg, 48%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 7.95 (s, 1H), 7.90-7.89 (m, 1H), 7.88-7.87 (m, 1H), 7.82-7.81 (m, 1H), 7.51-7.50 (m, 1H), 7.48-7.47 (m, 1H), 4.56 (s, 2H), 3.84 (t, J=5.4 Hz, 2H), 2.91 (t, J=5.4 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14]C2C(C3C=CC=CC=3)=C(OCCN)N=C(SC)N=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(C)(C)C.S1C=CC=C1S(Cl)(=O)=O>>[C:8]1([S:11]([NH2:14])(=[O:13])=[O:12])[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(-c2ccccc2)c(OCCN)n1
Agent: O=S(=O)(Cl)c1cccs1
Product: NS(=O)(=O)c1ccccc1

Procedure:
According to Example 4a) 100 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl]-benzenesulfonamide was reacted with 121 mg thiophene-2-sulfonylchloride to give 115 mg 4-tert.-butyl-N-[6-(2-(2-thiophenesulfonyl)-amino)-ethoxy)-2-methylsulfanyl-5-phenyl-pydmidin-4-yl]-benzenesulfonamide. LC-MS: tR=5.98 min, [M−1]−=617.39.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][CH:8]=1)C>C1COCC1.CO.O>[C:13]1([C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:19])=[O:5])=[CH:8][N:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
LiOH (38 mg, 0.93 mmol) was added to a stirred solution of 6-phenyl-nicotinic acid ethyl ester (140 mg, 0.62 mmol) in THF:MeOH:H2O (3:1:1, 2.8 mL), and the resulting mixture was stirred at room temperature overnight. The methanol and THF were evaporated from the reaction mixture, which was then diluted with water (2 mL), acidified with citric acid solution and the product was extracted with EtOAc. The organic layer was washed with saturated brine solution, dried over Na2SO4 and concentrated in vacuo to afford 100 mg (81.9% yield) of 6-phenyl-nicotinic acid (100 mg). LCMS purity: 98.1%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: COCCOC
Product: [O-][n+]1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 85.2 %

Procedure:
To a mixture of 4-chloropyridine-N-oxide (5.32 g, 41 mmol) and 4-trifluoromethylphenylboronic acid (9.36 g, 49.3 mmol) in anhydrous 1,2-dimethoxyethane (100 ml) was added tetrakis(triphenylphosphine)palladium (0) (1.5 g, 1.3 mmol) and saturated aqueous sodium carbonate solution (50 ml). Nitrogen was bubbled through the mixture for 5 minutes and the reaction was then heated with stirring at 100° C. for 15 hours under an atmosphere of nitrogen. The mixture was allowed to cool to room temperature and the solid was filtered off and washed with 1,2-dimethoxyethane (2×30 ml). The combined organic layers were evaporated under reduced pressure and triturated with diethyl ether (100 ml). The obtained solid was filtered off and dried on the sinter to give 4-(4-trifluoromethylphenyl)pyridine-N-oxide (8.36 g). This compound was suspended in phosphorous oxychloride (50 ml, 536 mmol) and the mixture was heated at 100° C. for 3 hours. After cooling to room temperature the homogeneous dark solution was evaporated under reduced pressure and repartitioned between chloroform and water (200 ml each). The pH was adjusted to 8 by portionwise addition of saturated aqueous sodium carbonate solution and the phases were separated. After two further extractions the combined organic extracts were washed with water and brine and dried over sodium sulfate. After filtration the compound was adsorbed onto silica gel and purified by flash chromatography (10% ethyl acetate-iso-hexane) to yield the title compound (5.5 g, 52%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][C@H:9]([CH3:13])[CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>ClCCl>[Cl:23][CH2:24][C:25]([N:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:8][C@H:9]1[CH3:13])=[O:26]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)CCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (3R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (3 g, 14.4 mmol) in dichloromethane (40 mL) was added triethylamine (2.0 mL, 14.4 mmol). The reaction was cooled to 0° C. and chloroacetyl chloride was added (1.1 mL, 14.4 mmol). The reaction was allowed to warm to ambient temperature and stirred for 2 hours. The reaction is diluted with dichloromethane and washed with 10% citric acid. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (3.9 g).
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=O)[C@@H:3]([CH3:5])[OH:4].[NH:19]1[CH2:30][CH2:29][CH2:28][C@H:20]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([N:19]1[CH2:30][CH2:29][CH2:28][C@H:20]1[C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[O:8])[C@@H:3]([CH3:5])[OH:4]
Reactant: C[C@@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 64 %

Procedure:
In the way described in B(1), 0.33 mol Z-Thr-OH and 0.35 mol H-Pro-OtBu are coupled with the aid of HOBt and DCCI in DMF. Yield 64%; melting point 65°-67° C. The Z-Thr-Pro-OtBu obtained in this way is hydrogenated in the way described above (see B.3.b.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)([O-:3])=[O:2].[Cu](C#N)[C:18]#[N:19].CN(C=O)C.C(N)CN>O.CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:18]#[N:19])=[CH:12][CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(Br)cc1
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CC(C)=O
Solvent: NCCN
Product: N#Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1

Procedure:
20 g (7.19 10-2 moles) of 4 nitro 4'bromobiphenyl, 11.6 of copper cyanide and 120 ml of DMF are placed in a 250 ml receptacle with a magnetic agitator. The mixture is refluxed for 5 h 30. It is then allowed to cool, acetone is added and the reaction medium is poured into 2 liters of water containing 2 g of ethylene diamine. A precipitate is formed. The solid is filtered out then washed in water and hexane. This raw product is redissolved in chloroform. The organic phase is dried on MgSO4, filtered and evaporated till dry. The solid obtained is recrystallized in an ethanol-chloroform mixture. This provides 13.16 g of product, yield ρ=81.7%, melting point=195° C.