Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][O:10][Si](C(C)(C)C)(C)C)[CH:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:18][N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CNc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(c1ccccc1)c1cccc(CCO)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
1-Bromo-3-[2-(tert-butyldimethylsilyloxy)ethyl]benzene (2.5 g, 7.96 mmol), N-methylaniline (1.02 g, 9.55 mmol), Pd2dba3 (364 mg, 0.4 mmol), Xantphos (691 mg, 1.19 mmol) and NaOtBu (727 mg, 9.55 mmol) were combined in toluene (12 mL), and the reaction was heated at 100° C. in the microwave for 90 min. The reaction was diluted with EtOAc, washed with brine, dried (MgSO4), and concentrated. The residue was stirred in 70% TFA/DCM (10 mL) for 2 h. The solution was concentrated and purified by silica gel chromatography (30% to 100% EtOAc/hexanes) to give 1.3 g (72%) of the title compound as a clear oil. 1H NMR (400 MHz, CDCl3): δ 1.53 (1H, br s), 2.81 (2H, t, J=6.5 Hz), 3.31 (3H, s), 3.83 (2H, t, J=6.5 Hz), 6.81 (1H, d, J=7.4 Hz), 6.86-6.89 (2H, m), 6.97 (1H, t, J=7.3 Hz), 7.04 (d, 2H, J=7.8 Hz), 7.18-7.29 (3H, m). [M+H] Calc'd for C15H17NO, 228. Found, 228.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>C1(C)C=CC=CC=1>[C:6]([NH:5][C@H:4]([CH:3]=[O:2])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](C=O)CCc1ccccc1
Temperature: -80 °C
Reaction time: 1.5 h

Procedure:
2.93 g of N-BOC homo phenylalanine methyl ester (10 mmol) are dissolved in 25 ml of absolute toluene under nitrogen and the solution is cooled to -80° C. 20 ml of -20% strength DIBA in toluene are added dropwise and the temperature maintained. Since the reaction was not complete after 1.5 h a further 3 ml of 20% strength DIBA were added.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][NH:19][C@@H:18]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[C@@H:18]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][N:26]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(-c2nccs2)c(C(=O)O)c1
Product: Cc1ccc(-c2nccs2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(thiazol-2-yl)benzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 475 [M+1]+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:32])[C:18]=1[CH:19]=[C:20]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[C:22](=[O:31])[O:21]1.[NH4+].[Cl-]>C(OCC)C.C1COCC1.O>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:32])[C:18]=1[CH:19]=[C:20]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[C:22]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)([OH:31])[O:21]1
Reactant: COc1ccc2c(c1)C(=O)OC2=Cc1c(Cl)cncc1Cl
Reactant: Brc1nccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(O)(c1nccs1)OC2=Cc1c(Cl)cncc1Cl
Temperature: -80 °C
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
A milky solution of 2-bromothiazole (5.6 g, 34.2 mmoles) in dry ethyl ether (17 ml) was added dropwise to a solution of n-butyl lithium (14.4 ml, 36 mmoles) in dry ethyl ether (50 ml), under N2 at −80° C. The reaction mixture was stirred at −80° C. for 15 minutes, then a solution of 3-(3,5-dichloro-pyridin-4-ylmethylene)-6-methoxy-3H-isobenzofuran-1-one (10 g, 31 mmoles), prepared as described in example 37, in dry THF (60 ml) was slowly added. After 45 minutes at −78° C., the resultant solution was treated with saturated NH4Cl, with water and brought to room temperature. The aqueous phase was separated and extracted with ethyl acetate, decoloured with charcoal, filtered over celite and concentrated under vacuum. The resultant foam was flash cromatographed (eluent petrolatum:ethyl acetate 6:4) obtaining 4.64 g of the title compound (yield: 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:7](=[O:20])[N:6]([CH2:21][C:22]([O:24]CC)=[O:23])[C:5]2=[O:27].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)[C:7](=[O:20])[N:6]([CH2:21][C:22]([OH:24])=[O:23])[C:5]2=[O:27]
Reactant: CCOC(=O)Cn1c(=O)c2cc(Cl)ccc2n(Cc2ccc(F)cc2)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cn1c(=O)c2cc(Cl)ccc2n(Cc2ccc(F)cc2)c1=O
Yield: 50.8 %

Procedure:
Into 50 ml of ethanol were dissolved 1.59 g of ethyl 6-chloro-1-(4-fluorophenyl)methyl-1,4dihydro-2,4-dioxo-3(2H)-quinazolineacetate, and after added 5 ml of aqueous solution containing 0.30 g of potassium hydroxide, the mixture was refluxed for 1 hour. After cooling by allowing to stand, ethanol was distilled off and the residue was dissolved by adding 30 ml of water, acidified with concentrated hydrochloric acid, and the deposits were collected by filtration. They were recrystallized from acetonitrile to obtain 0.75 g of title compound. m.p. 211°-212° C.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([O:11][C:12]([CH2:15][N:16]([CH2:18][CH2:19][CH:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:17])([CH3:14])[CH3:13])=[O:10])[CH:4]([C:33]2[CH:34]=[CH:35][CH:36]=[C:37]([N+:39]([O-:41])=[O:40])[CH:38]=2)[C:3]=1[C:42]([O:44][CH3:45])=[O:43].[C:46]1([S:52]([OH:55])(=[O:54])=[O:53])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CO>[CH3:1][C:2]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([O:11][C:12]([CH2:15][N:16]([CH2:18][CH2:19][CH:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH3:17])([CH3:13])[CH3:14])=[O:10])[CH:4]([C:33]2[CH:34]=[CH:35][CH:36]=[C:37]([N+:39]([O-:41])=[O:40])[CH:38]=2)[C:3]=1[C:42]([O:44][CH3:45])=[O:43].[S:52]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([O-:55])(=[O:54])=[O:53]
Reactant: O=S(=O)(O)c1ccccc1
Agent: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)CN(C)CCC(c2ccccc2)c2ccccc2)C1c1cccc([N+](=O)[O-])c1
Solvent: CO
Product: O=S(=O)([O-])c1ccccc1
Reaction time: 24 h

Procedure:
A larger scale production has been performed as follows. A solution of 48 g of lercanidipine free base in 96 ml of methanol was added with 12.7 g of benzenesulfonic acid in 22 ml of methanol at room temperature. The resulting suspension was filtered and evaporated at 55° C. to a final volume of 50 ml. The solution was then seeded with crystalline lercanidipine besylate, and allowed to stand at room temperature for 24 hours, followed by storage at 5 C for 6 days. The resulting compact mass of crystals was collected by suction, washed with 2×40 ml of methanol and dried under vacuum in the presence of P2O5. 51.1 g of lercanidipine besylate was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16]([O:18][C:19]3[C:28]4[C:23](=[C:24]([Cl:38])[C:25]([O:29][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:26][CH:27]=4)[N:22]=[C:21]([C:39]4[N:40]=[C:41]([NH:44][CH:45]([CH3:47])[CH3:46])[S:42][CH:43]=4)[CH:20]=3)[CH2:15][N:14]2[C:48](=[O:64])[CH:49]([NH:54][C:55]([O:57][CH:58]2[CH2:63][CH:62]3[CH:60]([CH2:61]3)[CH2:59]2)=[O:56])[C:50]([CH3:53])([CH3:52])[CH3:51])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4].[Li+].[OH-].CO.Cl>C1COCC1.O>[CH:60]12[CH2:61][CH:62]1[CH2:63][CH:58]([O:57][C:55]([NH:54][CH:49]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:48]([N:14]1[CH2:15][CH:16]([O:18][C:19]3[C:28]4[C:23](=[C:24]([Cl:38])[C:25]([O:29][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:26][CH:27]=4)[N:22]=[C:21]([C:39]4[N:40]=[C:41]([NH:44][CH:45]([CH3:46])[CH3:47])[S:42][CH:43]=4)[CH:20]=3)[CH2:17][CH:13]1[C:11]([NH:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:12])=[O:64])=[O:56])[CH2:59]2
Reactant: CCC1CC1(NC(=O)C1CC(Oc2cc(-c3csc(NC(C)C)n3)nc3c(Cl)c(OCCN4CCOCC4)ccc23)CN1C(=O)C(NC(=O)OC1CC2CC2C1)C(C)(C)C)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCC1CC1(NC(=O)C1CC(Oc2cc(-c3csc(NC(C)C)n3)nc3c(Cl)c(OCCN4CCOCC4)ccc23)CN1C(=O)C(NC(=O)OC1CC2CC2C1)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.9 %

Procedure:
1-({1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-2-(2-isopropylaminothiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid methyl ester (12 g, 13 mmol) was dissolved in THF (200 ml), LiOH (11 g, 260 mmol) in H2O (200 ml) was added, followed by MeOH (200 ml). The mixture was kept stirring at room temperature for 20 h. Upon completion of the reaction, 4 N HCl in H2O was added to adjust pH to 7 at 0° C. The mixture was extracted with EtOAc (2×400 ml). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give 1-({1-[2-(bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethyl-butyryl]-4-[8-chloro-2-(2-isopropylamino-thiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid as a yellow solid (11 g, 93% yield). LCMS found 911.52[M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]23[CH2:19][CH:17]([CH2:18]2)[C:16](=[O:20])[N:15]([CH2:21][CH2:22][CH3:23])[C:14]3=[O:24])=[CH:9][CH:8]=1.O>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]23[CH2:18][CH:17]([CH2:19]2)[C:16](=[O:20])[N:15]([CH2:21][CH2:22][CH3:23])[C:14]3=[O:24])=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCN1C(=O)C2CC(c3ccc(NS(C)(=O)=O)cc3)(C2)C1=O
Reaction time: 5 h

Procedure:
A solution of 0.31 ml of methanesulphonic acid chloride in 3 ml of methylene chloride is added at room temperature to a solution of 1.03 g of 1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione and 24 mg of 4-dimethylaaminopyridine in 10 ml of pyridine. After stirring for 5 hours, 50 ml of water are added, and the mixture is left to stand overnight at 0°-5°. Extraction is carried out with methylene chloride, and the organic phase is washed in succession with water, cold 2N hydrochloric acid, water, semi-saturated bicarbonate solution and water. After drying over magnesium sulphate, the mixture is filtered and concentrated by evaporation, and the residue is recrystallised from methanol. The title compound is obtained in the form of white crystals having a melting point of 159°-160°. Rf (hexane/ethyl acetate 1:1)=0.15.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[C:26]1([C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:12][CH2:11][C:7]2[N:6]=[C:5]([CH2:4][NH2:1])[CH:10]=[CH:9][CH:8]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: [N-]=[N+]=NCc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
A solution of 2-(azidomethyl)-6-(triphenylmethoxymethyl)pyridine (2.78 g, 6.8 mmol) in THF (25 mL) was treated with triphenylphosphine (1.96 g, 7.5 mmol), stirred at room temperature for 3 h, treated with water (184 μl, 10.2 mmol), stirred at room temperature for a further 7 days and concentrated in vacuo. The resulting oil was purified by chromatography [SiO2; EtOAc:MeOH:NH3 (1:0:0) to (9:1:0.2)] to give the title compound (2.33 g, 90%) as a yellow oil; NMR δH (400 MHz, CDCl3) 1.74 (2H, s), 3.90 (2H, s), 4.34 (2H, s), 7.14-7.33 (10H, m), 7.50-7.52 (6H, m) and 7.65-7.74 (2H, m); M/Z 381 (M+H)+
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=3[N:14]=[C:13]2[C:23]([F:26])([F:25])[F:24])=[CH:8][N:7]=1)=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:16]2[N:12]([C:9]3[CH:10]=[CH:11][C:6]([NH2:5])=[N:7][CH:8]=3)[C:13]([C:23]([F:26])([F:24])[F:25])=[N:14][C:15]=2[CH:20]=1
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1ccc(NC(=O)C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1ccc(N)nc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
To a solution of 2,2,2-Trifluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyridin-2-yl]-acetamide (100 mg, 0.25 mmol) in methanol (20 ml) was added K2CO3 (510 mg, 3.69 mmol). The resultant solution was allowed to stir overnight at 65° C. The reaction progress was monitored by LCMS. After completion, the reaction mixture was quenched by adding 30 ml of H2O. The resultant solution was extracted three times with 30 ml of EtOAc and the organic layers were combined and dried over Na2SO4. After removal of the drying reagent and the solvent, the residue was purified by SGC using 1:3 EtOAc/petroleum ether as eluents to provide 80 mg (79%) of 5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyridin-2-ylamine (gg) as a white solid. 1NMR (400 MHz, CDCl3) δ 8.11 (1H, s), 7.49 (1H, dd, J=2.16 Hz), 7.47 (1H, dd, J=2.16 Hz), 7.33 (1H, dd, J=8.8 Hz), 7.04 (1H, s), 6.69 (1H, dd, J=8.8 Hz), 5.08 (2H, s), 3.87 (3H, s) ppm.
Reaction SMILES: N1(O[C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:38]=3[N:39]=[CH:40][N:41]=2)[C@@H:16]2[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:17]2)C2C=CC=CC=2N=N1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>COCCOC>[N:48]1([C:11]2[N:41]=[CH:40][N:39]=[C:38]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:16]2[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:31])[CH3:32])[C@@H:18]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[CH2:17]2)[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: C1COCCN1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N4CCOCC4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
In a clean, dry reaction vial equipped with a stirring bar were placed O6-(benzotriazol-1-yl)-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol), Cs2CO3 (65.2 mg, 0.200 mmol) and dry DME (1.0 mL). Morpholine (17.5 μL, 0.200 mmol) was added, the reaction mixture was flushed with N2, and the mixture was allowed to stir at room temperature for 1 h. The reaction mixture was concentrated and the residue was dissolved in EtOAc. The mixture was washed with 10% aq citric acid, sat aq NaHCO3 and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. No additional purification was needed and 43 mg (78% yield) of the title compound was obtained. Rf (3% MeOH in CH2Cl2)=0.18. 1H NMR (500 MHz, CDCl3): δ 8.34 (s, 1H, Ar—H), 8.02 (s, 1H, Ar—H), 6.46 (t, 1H, H-1′, J=6.6), 4.59 (m, 1H, H-3′), 4.30 (br s, 4H, 2CH2), 4.01 (app q, 1H, H-4′, Japp˜3.4), 3.85-3.82 (m, 5H, H-5′ and 2CH2), 3.76 (dd, 1H, H-5′, J=11.0, 3.2), 2.59 (app quint, 1H, H-2′, Japp˜6.5), 2.42 (ddd, 1H, H-2′, J=13.2, 5.9, 3.9), 0.91 (s, 18H, tert-Bu), 0.09, 0.08, 0.076 (3 s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 153.9, 152.3, 150.6, 136.8, 120.4, 87.8, 84.1, 72.0, 67.0, 62.8, 45.6, 41.1, 26.0, 25.7, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C26H48N5O4Si2 (M++H) 550.3245. found 550.3222.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[F:39]>>[Cl:32][C:33]1[CH:34]=[C:35]([S:40]([NH:43][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:4]3[C:5]([CH3:13])=[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:2]([CH3:1])=[N:3]3)=[CH:19][CH:18]=2)=[O:24])(=[O:41])=[O:42])[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: NS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(F)c(Cl)c3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 3-chloro-4-fluorobenzenesulfonamide: 1H-NMR (CDCl3) δ 8.03-8.01 (1H, m), 8.00-7.79 (1H, m), 7.46-7.21 (10H, m), 6.14 (1H, br.s), 3.49-3.42 (2H, m), 2.84 (2H, t, J=6.7 Hz), 2.31 (3H, s), 2.23 (3H, s).
Reaction SMILES: C([O:8][C:9](=[O:27])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:26])[C@H:16]([CH3:25])[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:21]([O:20][C:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:27])=[O:8])=[O:26])[CH3:25])=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 92.4 %

Procedure:
N-t-butyloxycarbonyl-L-alanyl-L-proline benzyl ester (6.4 g, 17 m mole) was dissolved in methanol (100 ml). Hydrogen was passed for 3 hours through the solution in the presence of 10% palladium-carbon as a catalyst. The catalyst was removed by filtration and the solvent was distilled off under reduced pressure. The residue was crystallized in ethyl acetate-n-hexan to give N-t-butyloxycarbonyl-L-alanyl-L-proline (4.5 g, yield: 92.4%) having melting point of 155° to 157° C. and specific rotatory power [α]D25 =-90.5° (C=1, ethanol). The product gave a single spot on thin layer chromatography.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][NH:19][CH:20]3[C:28]4[C:23](=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[C:37]([N:19]([CH:20]1[C:28]2[C:23](=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)[CH2:18][C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: COc1cccc2c1CCC2NCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc2c1CCC2N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)C(C)=O
Reaction time: 1.5 h

Procedure:
To a solution of 1-(4,5-diphenyloxazol-2-yl)methylamino-2,3-dihydro-4-methoxy-1H-indene (0.22 g) and pyridine (0.2 ml) in dichloromethane (5 ml) was added acetyl chloride (0.15 ml) at 0° C. The mixture was stirred for 1.5 hours at the same temperature and partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water, sat. NaHCO3, and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give 1-[N-acetyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.08 g). MS (m/z): 439 (M+ +1) IR (Nujol): 1640 cm-1NMR (CDCl3, δ): 7.65-7.45 (4H, m), 7.40-7.20 (6H, m), 7.19-7.02 (1H, m), 6.82-6.60 (2H, m), 6.40 (0.5H, t, J=7.5 Hz), 5.56 (0.5H, t, J=7.5 Hz), 4.72 (0.5H, d, J=8.1 Hz), 4.42 (1H, m), 4.19 (0.5H, d, J=8.1 Hz), 3.81 (1.5H, s), 3.78 (1.5H, s), 2.37 (1.5H, s), 3.15-2.92 (1H, n), 2.90-2.64 (1H, m), 2.62-2.42 (1H, m), 2.40-2.10 (1H, m), 2.37 (1.5H, s), 2.35 (1.5H, s)
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].C[O-].[Na+].[Cl:12][C:13]1[CH:35]=[CH:34][C:16]2[C:17](=O)[C:18](=[CH:29]N(C)C)[CH2:19][N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:15]=2[CH:14]=1>CO.O>[NH2:7][C:6]1[N:8]=[CH:29][C:18]2[CH2:19][N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:15]3[CH:14]=[C:13]([Cl:12])[CH:35]=[CH:34][C:16]=3[C:17]=2[N:5]=1
Reactant: CN(C)C=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O
Reactant: N=C(N)N
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In two equal portions 14.4 g (80 mmole) of guanidine carbonate and 20 ml (82 mmole) of 4.12M methanol solution of sodium methoxide was added over 90 min to a solution of 3.6 g (10 mmole) of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one in 100 ml of methanol. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow oil. Crystallization of the oil with methylene chloride gave a white solid, mp 240°-241° C. Recrystallization from a mixture of ether and methylene chloride gave colorless needles, mp 240°-241° C.
Reaction SMILES: O1CCCC1.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=1.[H-].C([NH2+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)(=O)C>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(CCc2ccccn2)cc1
Agent: CC(C)C[NH2+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ccc(CCc2ccccn2)cc1
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
To an anhydrous tetrahydrofuran (50 mL) solution of methyl 4-(2-pyridin-2-yl-ethyl)benzoate 3.71 g, 15.4 mmol) described in Manufacturing Example 93-1-3 was added diisobutyl ammonium hydride (0.97 M toluene solution, 39.7 mL, 38.5 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere. After 30 minutes of stirring, 15% aqueous potassium sodium tartrate solution (100 mL) was added to the reaction mixture, and stirred for 30 minutes at room temperature. Ethyl acetate (100 mL) was added, and the organic layer and water layer were separated. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (3.16 g, 96%).