Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:19]=[N:20][C:21]=3F)[N:10]=2)=[CH:5][CH:4]=1.[F:44][C:45]1[CH:46]=[C:47]([NH2:53])[CH:48]=[N:49][C:50]=1[O:51][CH3:52].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH:19]=[N:20][C:21]=3[NH:53][C:47]3[CH:48]=[N:49][C:50]([O:51][CH3:52])=[C:45]([F:44])[CH:46]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)C(=O)OC(C)(C)C)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)C(=O)OC(C)(C)C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
Tert-butyl 2-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)-2-methylpropanoate (185 mg, 0.315 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Aldrich; 67.1 mg, 0.472 mmol) were dissolved in tetrahydrofuran (3.1 mL) and the resulting mixture was cooled to −60° C. and sodium bis(trimethylsilyl)amide, 1 M in THF (Aldrich; 944 μL, 0.944 mmol) was added. The resulting mixture was stirred at −60° C. for 1 h, and the reaction mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated in vacuo. Chromatographic purification of the residue (silica gel) with 100% hexanes to 50% EtOAc/hexanes to give the title compound (11% yield) as a yellow oil. m/z (ESI, +ve) 709.8 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1.[CH3:21][C:22]([CH3:24])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][N:14]([CH:22]([CH3:24])[CH3:21])[CH2:13][CH2:12]3)=[CH:4][CH:3]=1
Reactant: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Reactant: CC(C)=O
Product: CC(C)N1CCc2nn(C(C)C)c(-c3ccc(F)cc3)c2CC1

Procedure:
The title compound (92 mg) was prepared from 3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 190) and acetone as in Example 35. MS (ESI): exact mass calculated for C19H26FN3, 315.21. found, m/z 316.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.42-7.39 (m, 2H), 7.33-7.30 (m, 2H), 4.40 (m, 1H), 3.78-3.74 (m, 2H), 3.68-3.63 (m, 1H), 3.36-3.21 (m, 4H), 2.99-2.94 (m, 1H), 2.80-2.76 (m, 1H), 1.54-1.37 (m, 12H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([N+:21]([O-])=O)=[C:12]2[NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[F:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.O.C(OCC)(=O)C>C(O)C>[NH2:21][C:13]1[CH:14]=[N:15][C:16]2[C:11]([C:12]=1[NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[F:33])=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[C:18]([O:19][CH3:20])[CH:17]=2
Reactant: COc1cc2ncc([N+](=O)[O-])c(Nc3ccc(C#N)cc3F)c2cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2ncc(N)c(Nc3ccc(C#N)cc3F)c2cc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
4-(6-Benzyloxy-7-methoxy-3-nitroquinolin-4-ylamino)-3-fluorobenzonitrile (6.50 g, 14.62 mmol) and tin(II) chloride dihydrate (14.70 g, 65.15 mmol) were dissolved in ethanol (780 ml). The reaction solution was subsequently stirred at 70° C. for 30 min. When the reaction was complete (TLC, LC-MS), water (2 l) and ethyl acetate (1.5 l) was added, and the mixture was stirred vigorously for a further 30 min. The suspension obtained was filtered through kieselguhr. The aqueous phase was extracted again with ethyl acetate (1 l), and the combined organic phases were washed with water (500 ml). After the organic phase had been dried over Na2SO4, the solid material was filtered off with suction, and the filtrate was evaporated to dryness in vacuo, giving 4-(3-amino-6-benzyloxy-7-methoxyquinolin-4-ylamino)-3-fluorobenzonitrile (3.40 g, 8.2 mmol) as solid. MS: 415.1 (M+H+), TLC (HPTLC): Rf=0.47 (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][NH:11][N:10]=1.N#N.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].[O:36]([CH3:38])[Na]>C1COCC1.CO>[CH3:38][O:36][C:24]([N:11]1[N:10]=[C:9]([CH2:8][C:7]2[C:6]([Cl:21])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12]1)=[O:25]
Reactant: CO[Na]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2c(c1)CNN=C2Cc1c(Cl)cncc1Cl
Agent: N#N
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)N1Cc2cc(OC)ccc2C(Cc2c(Cl)cncc2Cl)=N1
Yield: 52 %

Procedure:
A solution of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1,2-dihydro-phthalazine (1 g, 3.1 mmoles), prepared as described in example 22, in THF (35 ml), under stirring and dry N2 at room temperature, was added with 1,1′-carbonyldiimidazole (0.55 ml, 3.41 mmoles). The mixture was refluxed for 1 hour. Dry CH3OH (2 ml) was added and the heating went on for further 2.5 hours. The mixture was cooled, poured into water/ice and extracted with CH2Cl2. The organic phases were washed with KHSO4, then with 5% NaOH, at last with water, anhydrified and concentrated to give a solid which was put in CH3OH with a catalytic amount of NaOCH3. The solution was refluxed for 1.5 hours, cooled, CH3OH was evaporated, the residue was taken up in water and CH2Cl2. The organic phases were washed with NaOH and water, anhydrified and concentrated to give a solid, which was triturated in CH3OH. 0.6 g of the title compound were obtained (yield: 52%). m.p.: 184-186° C.
Reaction SMILES: [CH:1]([C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1)=O.S([O-])(O)=O.[Na+].[C-:16]#[N:17].[K+].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C.O>[CH2:19]([NH:26][CH:1]([C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1)[C:16]#[N:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1(C=O)CC1
Reactant: [C-]#N
Reactant: NCc1ccccc1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(C(C#N)NCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 78.8 %

Procedure:
An eggplant type flask was charged with 501 mg of ethyl 1-formylcyclopropane-1-carboxylate and 2 ml of water to which were further added 1.13 g of sodium hydrogen sulfite and 345 mg of potassium cyanide. Thereto was added dropwise 564 mg of benzylamine dissolved in 5 ml of ethanol at room temperature, followed by 2.5 hours of stirring the reaction solution at 50° C. After confirming completion of the reaction, the reaction solution was mixed with ice water and extracted with ethyl acetate. Next, the resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and, after removing insoluble matter by filtration, concentrated under a reduced pressure. Thereafter, the resulting residue was subjected to a silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 717 mg (79%) of the title compound in the form of colorless oil. Spectrum data of the thus obtained oily product coincided with those of the compound of Inventive Example 2.
Reaction SMILES: [C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([NH2:28])[C:18]=3[C:19](=[O:21])[CH:20]=2)=[CH:11][C:10]=1[F:29])[CH2:5][CH2:6][CH2:7]I)(=[O:3])[CH3:2].Cl.[CH3:31][NH:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([NH2:28])[C:18]=3[C:19](=[O:21])[CH:20]=2)=[CH:11][C:10]=1[F:29])[CH2:5][CH2:6][CH2:7][N:32]([CH3:33])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N(CCCI)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(CCCN(C)C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 68.6 %

Procedure:
7.16 g (13.9 mmol) of the above 2-[4-[N-acetyl-N-(3-iodopropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one was dissolved in 150 mL of dimethylformamide under argon atmosphere, 5.68 g (69.5 mmol) of dimethylamine hydrochloride and 9.61 g (69.5 mmol) of potassium carbonate were added and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1-6:1-chloroform:methanol:aqueous ammonia=9:1:1) to give 4.13 g of 2-[4-[N-acetyl-N-(3-dimethylaminopropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one (yield: 69%).
Reaction SMILES: [Li+].[CH3:2][Si]([N-][Si](C)(C)C)(C)C.[CH:11]([Si:14]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1)([CH3:13])[CH3:12].Br[C:35]1[C:36](C)=[C:37]2[C:42](=[O:43])[NH:41][C:39](=[O:40])[C:38]2=[CH:44][CH:45]=1>C1COCC1>[O:43]=[C:42]1[C:37]2[C:38](=[CH:44][CH:45]=[CH:35][CH:36]=2)[C:39](=[O:40])[N:41]1[CH2:2][CH:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:15][Si:14]([CH:11]([CH3:12])[CH3:13])([CH:28]([CH3:30])[CH3:29])[CH:31]([CH3:33])[CH3:32])=[CH:18][CH:19]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)Cc1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Reactant: Cc1c(Br)ccc2c1C(=O)NC2=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of LiHMDS in THF cooled to −78° C. was added a cooled solution (−78° C.) of methyl 2-(4-((triisopropylsilyloxy)methyl)phenyl)acetate (E133) in THF via syringe. The solution was stirred at −78° C. for 30 min. Bromo-methyl phthalimide was added directly to the anion and the solution stirred for 2 h at −78° C. The reaction was then poured into NH4Cl(sat) and extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-20% EtOAc/Hexanes) gave pure methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanoate (E134).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[CH2:13])[C:8]([C@@H:14]([N:16]1[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]1=[O:26])[CH3:15])=[CH:7]2.[OH2:27].C[N+]1([O-])CC[O:32]CC1>C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O.O.[O-][Os]([O-])(=O)=O.[K+].[K+]>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]([OH:32])[CH2:13][OH:27])[C:8]([C@@H:14]([N:16]1[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]1=[O:26])[CH3:15])=[CH:7]2
Reactant: C=Cc1nc2c(Cl)cccc2cc1[C@H](C)N1C(=O)c2ccccc2C1=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Agent: O=[Os](=O)([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CCOC(C)=O
Product: C[C@@H](c1cc2cccc(Cl)c2nc1C(O)CO)N1C(=O)c2ccccc2C1=O
Reaction time: 0.08 h

Procedure:
To a stirred solution of (S)-2-(1-(8-chloro-2-vinylquinolin-3-yl)ethyl)isoindoline-1,3-dione (200 mg, 0.55 mmol) in THY (5 mL) and water (1.0 mL) was added potassium osmate(VI) dihydrate (10.2 mg, 27.6 μmol). The reaction was stirred for 5 minutes and then NMO (64.6 mg, 0.55 mmol) was added. The reaction was stirred for 3 hours and then it was diluted with ethyl acetate (80 mL) and 1.0 M aqueous citric acid (40 mL). The separated aqueous layer was extracted with ethyl acetate (140 mL) and the combined organic layers were washed with brine (40 mL), dried (MgSO4), filtered and evaporated in vacuo to give 2-((S)-1-(8-chloro-2-(1,2-dihydroxyethyl)quinolin-3-yl)ethyl)isoindoline-1,3-dione. The product was used without further purification in the next step. 1H NMR (400 MHz, CDCl3) δ ppm 8.77 (1H, d, J=11.7 Hz), 7.61-7.88 (6H, m), 7.49 (1H, q, J=8.1 Hz), 5.95-6.17 (1H, m), 5.22-5.32 (1H, m), 4.02-4.26 (2H, m), 1.94-1.97 (3H, m). Mass Spectrum (ESI) m/e=396.9 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:26][C:25]2[CH:28]=[CH:29][C:30]([F:31])=[C:23]([F:22])[CH:24]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(CBr)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccc(F)c(F)c2)cc1
Yield: 57.2 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 3,4-difluoro-benzyl bromide (145 mg, 0.6 mmol) to afford the title product, (120 mg, 55% yield); LCMS; 100% APCI+, Calcd: 419.5; Found m/z: 421.4 (M+2); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.09 (m, 4H), 3.28-3.46 (m, 2H), 3.69-3.91 (m, 1H), 4.02-4.18 (m 2H), 4.95 (s, 2H), 6.84-6.88 (m, 4H), 7.55-7.28 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.1 %

Procedure:
To a solution of 4-(4-Chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (80 mg, 67%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[I-].[K+].C[N:30]([CH:32]=O)C>C1(N)CCCCC1>[CH:32]1([NH:30][CH2:2][C:3]2[O:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]4[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]5[CH2:26][CH2:25]5)=[O:22])[CH:15]=4)=[CH:10][CH:9]=3)=[N:5][N:4]=2)[CH2:12][CH2:13][CH2:8][CH2:9][CH2:10]1
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Agent: [I-]
Agent: [K+]
Solvent: NC1CCCCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNC3CCCCC3)o2)cc1

Procedure:
4′-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 45) (37 mg) and potassium iodide (5 mg) were mixed in cyclohexylamine (2 ml) and DMF (2 ml) and the reaction stirred at room temperature for 18 hours. The solvents were evaporated under vacuum and the residue purified by bond-elut (silica), eluting with an ethyl acetate/cyclohexane gradient. After evaporation of the solvent this gave 4′-{5-[(cyclohexylamino)methyl]-1,3,4-oxadiazol-2-yl}-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([OH:22])=O)=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O.C(#N)C>[CH3:27][O:26][N:25]([CH3:24])[C:20]([C:11]1[C:12](=[O:19])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)[CH:10]=1)=[O:22]
Reactant: CNOC
Reactant: O=C(O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Yield: 90.9 %

Procedure:
9.45 g (26.3 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 2.82 g (28.9 mmol) of N,O-dimethylhydroxylamine hydrochloride, 22 mL (16 g, 158 mmol) of triethylamine and 18.8 mL (20.1 g, 31.6 mmol) of 50% 1-propanephosphonic acid cyclic anhydride were sequentially added to 250 mL acetonitrile at rt. After 1 h 400 mL of water were added and the mixture was extracted two times with 300 mL DCM. Combined organic layers were evaporated and the residue purified on silica flash column using 0-15% methanol in EtOAc to give 9.62 g of the product as an off-white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:22](=[O:23])[N:21]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.N1C=CC=NC=1>C(O)C.[Pd]>[CH:24]1([N:21]2[C:22](=[O:23])[C:17]3[CH:16]=[N:15][C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[N:19][C:18]=3[CH2:20]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1c2cnc(N3CCN(Cc4ccccc4)CC3)nc2CN1C1CCCCC1
Agent: [Pd]
Solvent: CCO
Solvent: c1cncnc1
Product: O=C1c2cnc(N3CCNCC3)nc2CN1C1CCCCC1
Yield: 99.4 %

Procedure:
Dissolved in 30 ml of ethanol was 1.2 g (3.07 mmol, Referential Example 79) of 2-(4-benzylpiperazino)-6-cyclohexyl-5-oxo-5,6-dihydro(7H)pyrrolo-[3,4-d]pyrimidine, followed by an addition of 0.16 g of 10% Pd-C. The pyrimidine derivative was hydrogenated at 60° C. After completion of the reaction, Pd-C was filtered off and ethanol was distilled off to obtain 0.92 g of the above-identified compound as crystals (yield: about 100%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:16])=[C:4]([NH2:15])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CC(O)=O.[N:21]([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>O>[Br:1][C:2]1[C:3]2[NH:16][N:21]=[N:15][C:4]=2[C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CN1CCN(c2ncc(Br)c(N)c2N)CC1
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN1CCN(c2ncc(Br)c3[nH]nnc23)CC1
Temperature: 10 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A 250 mL round bottom flask was charged with 5-bromo-2-(4-methylpiperazin-1-yl)pyridine-3,4-diamine (1.2 g, 4.2 mmol) and CH3COOH (10 mL). To the above was added dropwise a solution of NaNO2 (0.30 g, 4.3 mmol) in water (1 mL) at 10° C. The resulting mixture was stirred at 10° C. for 1 h. Work-up: the reaction mixture was basified to pH 8 by saturated aqueous Na2CO3 and extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 10% MeOH in CH2Cl2, to afford 1.1 g (88%) of the product as a white solid. MS m/z: 297 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:14]=[CH:13]2)[CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: OCC[C@@H](c1cccc(Br)c1)N1CCc2cccc(OCc3ccccc3)c21
Solvent: CCOC(C)=O
Product: OCC[C@@H](c1cccc(Br)c1)n1ccc2cccc(OCc3ccccc3)c21
Yield: 74 %

Procedure:
The title compound was prepared from (3S)-(+)-3-(3-bromophenyl)-3-(7-benzyloxyindolin-1-yl) propan-1-ol (13b) by a sequence analogous to that described immediately above. Column chromatography (ethyl acetate--light petroleum (b.p. 40°-60° C.), 1:4) provided the title compound (74%) as a yellow/brown oil; [α]D22 +188 (c=0.007 gml-1, CHCl3).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=2[CH2:5][CH2:4]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].CCN(C(C)C)C(C)C>C1COCC1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[C:9](=[O:10])[CH:3]([CH2:2][O:1][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:4][CH2:5][C:6]3[CH:23]=[CH:22][CH:21]=[CH:20][C:7]2=3)=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN2C(=O)C(CO)CCc3ccccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(COS(C)(=O)=O)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 3-hydroxymethyl-1-(4-methoxy-benzyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (0.26 mmol) in 2 mL of anhydrous THF at 0° C. is added MsCl (0.39 mmol) and DIEA (0.47 mmol). After the addition, the mixture is allowed to warm up to room temperature and then stirred for 1 hour. The solvent is removed under vacuum and the residue is treated with water (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers are concentrated and the residue is purified by flash column chromatography (silica gel) to provide methanesulfonic acid 1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylmethyl ester as white crystals. Yield: 90%. MS: (ES+): 390[M+1].
Reaction SMILES: [F:1][C:2]([F:41])([C:37]([F:40])([F:39])[F:38])[C@@H:3]([NH:11][C@@H:12]([CH2:16][S:17]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:13]([OH:15])=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.P(CCC(O)=O)(CCC(O)=O)CCC(O)=O.Cl>ClCCl>[F:41][C:2]([F:1])([C:37]([F:38])([F:39])[F:40])[C@@H:3]([NH:11][C@@H:12]([CH2:16][SH:17])[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1
Reactant: O=C(O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)N[C@@H](c1ccc(F)cc1)C(F)(F)C(F)(F)F
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: O=C(O)CCP(CCC(=O)O)CCC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@H](CS)N[C@@H](c1ccc(F)cc1)C(F)(F)C(F)(F)F
Reaction time: 4 h

Procedure:
To a solution of 2(R)-[2,2,3,3,3-pentafluoro-1-(S)-(4-fluorophenyl)propylamino]-3-tritylsulfanylpropionic acid (6.92 g, 12 mmol) in dichloromethane (10 mL), triethylsilane (3.73 mL, 23.4 mmol) and TFA (3.61 mL, 46.9 mmol) were added at room temperature. The reaction mixture was stirred for 4 h. The solvent and volatiles were evaporated on rotovap, benzene was added to the residue and the mixture was evaporated again to ensure complete removal of excess TFA. The residue was dissolved in 1 N NaOH (50 mL) and extracted with hexanes. To the resulting solution, P(CH2CH2CO2H)3.HCl (0.343 g, 1.2 mmol) was added, and a 0.2 M stock solution of 2(R)-[2,2,3,3,3-pentafluoro-1-(S)-(4-fluorophenyl)propylamino]-3-mercaptopropionic acid was obtained.