Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13]3[N:22]=[C:21]([NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[N:28]=[CH:27]5)[C:20]4[C:15](=[CH:16][C:17]([O:41][CH3:42])=[C:18]([OH:40])[CH:19]=4)[N:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:44][CH2:45][Cl:46].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:46][CH2:45][CH2:44][O:40][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:41][CH3:42])[N:14]=[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=1)[N:22]=[C:21]2[NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[N:28]=[CH:27]2
Reactant: ClCCBr
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 92.9 %

Procedure:
A mixture of tert-butyl 5-(2-[(3-phenyl)phenyl]-6-hydroxy-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (1.5 g, 2.68 mmole), 1-bromo-2-chloroethane (1.32 g, 0.76 mL, 9.17 mmole), K2CO3 (1.55 g, 11.21 mmole), and DMF (15 mL) was stirred at 85° C. for 2.5 h. The mixture was poured onto ice-water and the crude product was filtered. The product was then dissolved in a mixture of CH2Cl2 and CH3OH and the solution was concentrated in vacuo to give tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (1.55 g, 2.49 mmol, 93%). HPLC retention time 8.22 mins.
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][S:7][C:8]1[S:9][C:10]([CH:16]=O)=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14].[NH2:18]O.Cl.C(O)=O>O>[CH3:6][S:7][C:8]1[S:9][C:10]([C:16]#[N:18])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: NO
Reactant: CSc1sc(C=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CSc1sc(C#N)cc1[N+](=O)[O-]

Procedure:
A sodium methyl mercaptide solution was prepared by adding 5 ml of methylmercaptan to 1.75 g of Na in 60 ml of absolute ethanol. While stirring and cooling this solution to below 10° C. it was added to a solution of 17.6 g of 2-bromo-3-nitro-5-formylthiophene in 200 ml of ethanol. After stirring at room temperature for another 2 hours, 200 ml of water were added, after which the formed precipitate was sucked off, washed with water-ethanol mixture (1:1 v/v), and recrystallized from isopropanol. 6.5 g of 2-methylthio-3-nitro-5-formylthiophene of melting point 129°-131° C. were obtained. Then 2.35 g of NaHCO3, 3.1 g of 2-methylthio-3-nitro-5-formylthiophene, and 1.2 g of NH2OH.HCl were added successively to 50 ml of formic acid. The reaction mixture was refluxed for 1 hour, after which, water was added and the formed precipitate was sucked off. After recrystallization from isopropanol the desired 2-methylthio-3-nitro-5-cyanthiophene was obtained in a yield of 2.3 g; melting point 150° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[C:11]([NH:13][C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.CN([CH:48]=[O:49])C>C1COCC1>[O:1]([C:8]1[CH:25]=[CH:24][CH:23]=[C:10]2[C:9]=1[CH:48]([OH:49])[N:13]([C:14]([CH3:15])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:22])[C:11]2=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)c1cccc(Oc2ccccc2)c1)c1ccccc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2cccc(Oc3ccccc3)c2C1O
Yield: 90.1 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-phenoxy-N-(1-methyl-1-phenylethyl)benzamide (4.00 g, 12.1 mmol) was dissolved in THF (160 mL), and the solution was treated with TMEDA (5.80 mL, 38.7 mmol), sec-butyllithium-hexane solution (0.99 mol/L, 39.0 mL, 38.7 mmol) and DMF (2.10 mL, 26.6 mmol), followed by purification by slurry using diisopropylether to obtain 4-phenoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (3.92 g, yield 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)/[C:5](=[N:7]\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[NH2:6].Cl[CH2:18][CH:19]=O.C(=O)(O)[O-].[Na+].CC(O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:18]=[CH:19][N:6]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=CCCl
Reactant: N/C(=N/c1ccccc1)c1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Brc1cccc(-c2nccn2-c2ccccc2)c1
Temperature: 25 °C
Yield: 37 %

Procedure:
(E)-3-bromo-N′-phenylbenzimidamide (6.95 g, 25.3 mmol), 2-chloroacetaldehyde (6.94 g, 44.2 mmol) and sodium bicarbonate (5.30 g, 63.1 mmol) were charged into the reaction flask with 200 mL of 2-propanol. This reaction mixture was heated at reflux for 18 h. The reaction mixture was cooled to room temperature, was diluted with 200 mL of water then was extracted with ethyl acetate. The extracts were washed with aqueous lithium chloride then were dried over magnesium sulfate. These dried extracts were then filtered and stripped under vacuum. The crude residue was passed through a silica gel column using 30-35% ethyl acetate/hexanes yielding 2-(3-bromophenyl)-1-phenyl-1H-imidazole (2.8 g, 9.36 mmol, 37% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][C:22](O)=O)=[CH:18][CH:17]=1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[CH:26][C:16]([F:15])=[CH:17][CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1ccc(F)cc1
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(F)cc3)nc2n(CC)c1=O
Yield: 48.3 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.31 g (13.9 mmol) of 4-fluorocinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 2.00 g (yield 51%) of Compound 146 as colorless columns.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([Cl:13])=[CH:11][NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:14](N1C=CN=C1)(=[O:16])[CH3:15]>CCOCC.O>[C:14]([N:10]1[CH:11]=[C:12]([Cl:13])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:9]1)(=[O:16])[CH3:15]
Reactant: CC(=O)n1ccnc1
Reactant: Clc1cccc(-c2c[nH]cc2Cl)c1
Solvent: CCOCC
Solvent: O
Product: CC(=O)n1cc(Cl)c(-c2cccc(Cl)c2)c1
Yield: 57.8 %

Procedure:
The mixture of 6.5 g of 3-(3-chlorophenyl)-4-chloropyrol and 10.1 g of N-acetylimidazole was heated for one hour at 100°-110° C. After cooling, the reaction mixture was dissolved in a mixture of 200 ml of ether and 20 ml of water and the resulting ether solution was treated as in Example 4 to obtain 4.5 g of the desired product (colorless crystal, m.p. 88°-90° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:38])[N:15]=[C:16]([NH:17][CH2:18][C@H:19]([NH:27]C(OCC3C=CC=CC=3)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:11]=2[CH:10]=[CH:9]1)[CH3:2].C(O)(=O)C>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:38])[N:15]=[C:16]([NH:17][CH2:18][C@H:19]([NH2:27])[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C:11]=2[CH:10]=[CH:9]1)[CH3:2]
Reactant: CCOC(=O)CCCn1ccc2c(NC[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)nc(C)nc21
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CCCn1ccc2c(NC[C@H](N)C(=O)OC(C)(C)C)nc(C)nc21

Procedure:
709 mg of 4-[4-((2S)-2-benzyloxycarbonylamino-2-tert-butoxycarbonyl-ethylamino)-2-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-butyric acid ethyl ester were dissolved in 40 ml of ethanol and 1 ml of acetic acid and were hydrogenated over 100 mg of Pd/C (10%) during 4 h at room temperature. The catalyst was removed by filtration, the solvent was removed in vacuo. The residue was dissolved in 60 ml of DCM and stirred with 10 ml of brine and additional 5 g of NaHCO3. The phases were separated, the aqueous phase was extracted with DCM, the combined organic phases were dried over MgSO4, filtered and the solvent was removed in vacuo. Yield: 475 mg.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Cl[C@@H:21]([C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH3:22]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][C@H:21]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[CH3:22])=[N:6][C:5]=2[N:19]=1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: C[C@@H](Cl)c1ncccc1F
Product: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2ncccc2F)nc2nc(N)sc12
Yield: 38.8 %

Procedure:
The title compound was prepared using General method A starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (348 mg, 1.16 mmol) and 2-((R)-1-chloroethyl)-3-fluoro-pyridine (240 mg, 1.5 mmol). Purification by flash column chromatography (eluent DCM: methanol gradient) resulted in 190 mg (47% yield) of the title compound with a diastereomeric excess of 60%.
Reaction SMILES: [F-].[K+].[Br:3][C:4]1[N:8]2[N:9]=[C:10](Cl)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:21]2[C@@H:25]([O:26][Si](C(C)C)(C(C)C)C(C)C)[CH2:24][CH2:23][NH:22]2)[CH:18]=[CH:19][CH:20]=1>CS(C)=O.CO>[Br:3][C:4]1[N:8]2[N:9]=[C:10]([N:22]3[CH2:23][CH2:24][C@H:25]([OH:26])[CH:21]3[C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=3)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CC(C)[Si](O[C@H]1CCNC1c1cccc(F)c1)(C(C)C)C(C)C
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: O[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1c1cccc(F)c1
Temperature: 110 °C

Procedure:
In step 3-4, KF (100 mg, 1.72 mmol) and 3-bromo-6-chloroimidazo[1,2-b]pyridazine (12-1) (700 mg, 3.0 mmol) were added to a solution of (3S)-2-(3-fluorophenyl)-3-(triisopropylsilyloxy)pyrrolidine (4-3) (700 g, 2.0 mmol) in 3 mL of DMSO. The resulting slurry was heated to 110° C. for 6 hours and then cooled, diluted with 8 mL of MeOH and purified using reverse phase C-18 chromatography (water/acetonitrile 90:10 to 10:90 gradient) to furnish (3S)-1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2-(3-fluorophenyl)pyrrolidin-3-ol (3-4) as a solid (as a mixture of diastereomers). 1H NMR (400 MHz, D6 acetone) δ ppm 8.20 (app t, J=6.5 Hz, 1H), 7.85-6.70 (m, 6H), 5.05 (app d, J=5.5 Hz, 1H), 4.68 (app q, J=7.5 Hz, 1H), 4.30 (br s, 1H), 4.01-3.92 (m, 1H), 3.82-3.70 (m, 1H), 2.35-1.87 (m, 2H). LCMS observed m/z 377.1, 379.1 major ion.
Reaction SMILES: [CH:1]1([S:7]([CH2:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].C1(C)C=CC(S([N:33]=[N+:34]=[N-])(=O)=O)=CC=1>C(O)C.O>[CH:1]1([S:7]([C:10]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[N+:33]=[N-:34])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COc1ccc(S(=O)(=O)CS(=O)(=O)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C2CCCCC2)cc1
Reaction time: 0.08 h

Procedure:
3.0 g of the cyclohexylsulfonyl-(4-methoxyphenylsulfonyl)methane prepared in (2), was put into a flask, and 100 mL of ethanol was added thereto, followed by stirring. Further, to this solution, 8.0 g of a 5 wt % ethanol solution of sodium hydroxide was added, followed by stirring. This reaction solution was cooled to from -5° C. to -10° C., and 35 mL of pure water was added thereto. Then, 10 mL of the ethanol solution containing 2.0 g of p-toluenesulfonylazide obtained in Reference Example 2, was dropwise added thereto over a period of 5 minutes, and the mixture was stirred for 3 hours and left to stand overnight. Then, the precipitate was collected by filtration to obtain crude crystals. The crude crystals were re-crystallized from ethanol to obtain cyclohexylsulfonyl-(4-methoxyphenylsulfonyl)diazomethane.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:20]/[C:21](=[O:30])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1[CH2:19][CH2:20][C:21](=[O:30])[CH2:22][O:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)COc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(CC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)COc1ccccc1

Procedure:
(3aR,4R,5R,6aS)-2-Oxo-4-((E)-3-oxo-4-phenoxybut-1-enyl)hexahydro-2H-cyclopenta[b]furan-5-yl benzoate, prepared in Step A, is dissolved in ethyl acetate and 10% Pd/C is added to the solution under a nitrogen atmosphere. The solution is flushed with hydrogen gas and subsequently stirred under a hydrogen atmosphere until starting material is consumed as judged by TLC. The crude reaction mixture is filtered through Celite and the solvent is removed under reduced pressure. The crude product is purified by flash chromatography on regular silica gel eluted with ethyl acetate-hexanes to afford the title intermediate.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:31]([O:32][CH3:33])=[CH:30][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[CH:6]=1)[N:14]=[CH:13][C:12]([C:17]#[N:18])=[C:11]3[NH:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([Cl:28])=[CH:22][C:21]=1[Cl:29].[NH:34]1[CH:38]=[CH:37][N:36]=[N:35]1.[OH-].[Na+]>CN(C)C=O>[Cl:29][C:21]1[CH:22]=[C:23]([Cl:28])[C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:11]1[C:10]2[C:15](=[CH:16][C:7]3[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:35]4[N:36]=[CH:37][CH:38]=[N:34]4)[C:31]([O:32][CH3:33])=[CH:30][C:8]=3[CH:9]=2)[N:14]=[CH:13][C:12]=1[C:17]#[N:18]
Reactant: c1c[nH]nn1
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCn5nccn5)c(OC)cc4cc23)c(Cl)cc1Cl
Temperature: 80 °C
Yield: 21.4 %

Procedure:
A mixture of 0.31 g (0.62 mmol) of 8-(2-chloroethoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.36 mL (6.1 mmol) of 1H-1,2,3-triazole and 0.11 g (2.8 mmol) of sodium hydroxide powder in 5 mL of N,N-dimethyl formamide is heated at 80° C. for 4.5 hours, then cooled and poured on to ice. The solid is collected by filtration, washed with water and dried. The two isomers are separated by silica gel flash chromatography, using first 7:3 ethyl acetate/hexane, then a 100:0 to 9:1 gradient of ethyl acetate/methanol. The less polar material, 0.071 g of 4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxy-8-(2-[1,2,3]triazol-2-yl-ethoxy)benzo[g]quinoline-3-carbonitrile, is obtained as yellow solid, mp 285–287° C.
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[CH2:11]([NH:15][C:16](=[O:49])[C@H:17]([CH3:48])[CH2:18][C@H:19]([OH:47])[C@@H:20]([NH:39]C(OC(C)(C)C)=O)[CH2:21][C@@H:22]([CH:36]([CH3:38])[CH3:37])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH2:33][C:34]#[N:35])[CH:25]=1)[CH2:12][CH2:13][CH3:14]>ClCCl>[CH2:11]([NH:15][C:16](=[O:49])[C@H:17]([CH3:48])[CH2:18][C@H:19]([OH:47])[C@@H:20]([NH2:39])[CH2:21][C@@H:22]([CH:36]([CH3:37])[CH3:38])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH2:33][C:34]#[N:35])[CH:25]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCC#N)c1)C(C)C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)C[C@H](Cc1ccc(OC)c(OCC#N)c1)C(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.5 ml of a mixture of trifluoroacetic acid/dichloromethane=1:3 are added at 0° C., with stirring, to a solution of 35 mg of N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-cyanomethoxy-4-methoxy-phenyl)-octanoic acid (N-butyl)-amide in 1 ml of dichloromethane, and the mixture is stirred for a further 3 hours at 0° C. and then concentrated by evaporation. The residue is purified by FC (5 g of silica gel, dichloromethane/methanol=9:1). This yields the title compound: Rf (dichloromethane/methanol=9:1)=0.19; Rt (I)=19.59 minutes; FAB-MS(M+H)+ =448.
Reaction SMILES: [Si:1]([O:8][NH2:9])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([S:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]3[C:32](O)=[O:33])(=[O:25])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>C(Cl)Cl>[O:8]([NH:9][C:32]([CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][N:26]1[S:23]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=2)[CH2:18][CH2:19]1)(=[O:25])=[O:24])=[O:33])[Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)ON
Reactant: O=C(O)C1CCCCN1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)ONC(=O)C1CCCCN1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
O-(tert-butyldimethylsilyl)hydroxylamine (57 mg, 0.39 mmol) and 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (59 mg, 0.31 mmol) were added to a solution of 1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxylic acid (100 mg, 0.26 mmol), [prepared as described above] in methylene chloride (4 ml). The reaction mixture was stirred overnight at RT and then diluted with methylene chloride. The solution was washed with water, 10% citric acid, and brine, and dried over MgSO4. After the organics were removed the residue was chromatographed (SiO2, 2030% ethyl acetate/hexane) to give N-tert-butyldimethylsiloxy-1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxamide as a colorless foam (56%).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13](Cl)[N:14]3[C:19]([CH:20]=2)=[C:18]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])[C:17](=[O:29])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC.C(OCC)(=O)C>[ClH:27].[C:1]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[Cl:31])[N:14]3[C:19]([CH:20]=2)=[C:18]([C:21]2[C:22]([Cl:28])=[CH:23][CH:24]=[CH:25][C:26]=2[Cl:27])[C:17](=[O:29])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(C)(C)N1CC=C(c2cc(Cl)n3ccc(=O)c(-c4c(Cl)cccc4Cl)c3c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)N1CC=C(c2cc(-c3ccccc3Cl)n3ccc(=O)c(-c4c(Cl)cccc4Cl)c3c2)CC1
Temperature: 80 °C
Yield: 73.4 %

Procedure:
To a solution of 8-(1-tert-butyl-1,2,3,6-tetrahydropyridin-4-yl)-6-chloro-1-(2,6-dichlorophenyl)-2H-quinolizin-2-one (57 mg) in DME was added 2-chlorophenylboronic acid (38 mg), palladium tetrakis triphenylphosphine (14 mg) and 2N sodium carbonate (0.36 mL). The mixture was heated to 80° C. for a couple of hours, then cooled to room temperature, and diluted with ethyl acetate/saturated aqueous sodium bicarbonate. The organic layers were dried over magnesium sulfate and concentrated. The residue was purified by silica gel (100% acetone). The free base was dissolved in methylene chloride and 3 eq. of HCl (1N in ethyl ether) was added to give the HCl salt (26 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.[C:45]1([CH:51]2[CH:55](O)[CH2:54][CH2:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1.CCCCCC>[C:45]1([C@H:51]2[CH2:55][CH2:54][CH2:53][C@H:52]2[N:38]2[C:34](=[O:44])[C:35]3[C:36](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:37]2=[O:39])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC1CCCC1c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CCC[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
Scheme IB, step B: A 500 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, reflux condenser, addition funnel and a nitrogen blanket is charged with triphenylphosphine (16.19 g, 61.73 mmol) and THF (200 mL). To the solution at 0° C. was added dropwise, a solution of diisopropyl azodicarboxylate (12.15 mL, 61.73 mmol) dissolved in THF (30 mL) over a period of 10 minutes. A massive precipitate formed immediately after addition. To the slurry was then added solid phthalimide (9.08 g, 61.73 mmol), followed by a solution of 5-phenylcyclopentane-1-ol (10.0 g, 61.73 mmol) dissolved in THF (30 mL) over a period of 20 minutes maintaining temperature at 0° C. to 5° C. (reaction mixture went into solution by the end of alcoholic substrate addition). Reaction was then stirred at 0° C. for 4.0 hours and brought to room temperature overnight for convenience. Quenched reaction with water (200 mL) and extracted organics with chloroform (200 mL). Washed the organic with water (100 mL) and dried with anhydrous magnesium sulfate. Subsequent filtration and concentration under reduced pressure afforded an oil which solidified on equilibrating to room temperature. To the precipitate was then added hexane (250.0 mL) with vigorous stirring. Filtered off triphenylphosphine oxide precipitate and concentrated filtrate to an oil. Silica gel plug filtration of the oil with 1:1 ethyl acetate:hexanes and subsequent concentration of product fractions afforded an off white precipitate of (+,−) Cis-2-(2-phenyl-cyclopentyl)-isoindole-1,3-dione (mass=12.5 g, 69.6%); 1H nmr (CDCl3) 6 1.6-1.8 (m, 1H), 2.0-2.1 (m, 1H), 2.2-2.35 (m, 2H), 2.4-2.68 (m, 2H), 3.39-3.5 (m, 1H), 5.0-5.1 (m, 1H), 6.9-7.15 (aromatic, 5H), 7.52-7.64 (aromatic, 4H); 13C (CDCl3) 6 25.4, 28.89, 30.56, 50.34, 54.60, 122.89, 126.44, 128.01, 128.41, 131.67, 139.68, 168.86).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[CH:26]=[C:25]([NH:27]CC4C=CC(OC)=CC=4)[N:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[CH:26]=[C:25]([NH2:27])[N:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COc1ccc(CNc2cc3c(Nc4ccc(OCc5ccccn5)c(Cl)c4)ncnc3cn2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cn1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To a stirred heterogeneous mixture of compound 212 (2.88 g, 5.77 mmol) and DCVI (60 ml) was added trifluoroacetic acid (4.38 ml, 57.7 mmol), followed by anisole (1.27 ml, 11.5 mmol), and the mixture was stirred further at room temperature. After 72 h another batch of trifluoroacetic acid (4.38 ml, 57.7 mmol) was added and stirred further for 49 h. It was poured into petroleum ether (250 ml) and stirred at room temperature for ca. 20 min. Petroleum ether layer was decanted and discarded. The process was repeated with more petroleum ether (250 ml). The solid left behind was dissolved in acetone (150 mL) and 5M NH3 (125 ml) added at 0° C. The mixture was stirred at room temperature for 30 min. The solid was collected and washed successively with acetone/water (1:4) (5×30 ml), petroleum ether/ethyl acetate=3:1 (5×30 ml), and dried to give N4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyrido[3,4-d]-pyrimidine-4,6-diamine (221) (1.94 g, 89%), mp 247-250° C.; 1H NMR. δ [(CD3)2SO] 9.64 (s, 1H), 8.68 (s, 1H), 8.62-8.56 (m, 1H), 8.33 (s, 1H), 8.06 (d, J=2.6 Hz, 1H), 7.88 (td, J=7.7, 1.8 Hz, 1H), 7.73 (dd, J=9.0, 2.6 Hz, 1H), 7.58 (br d, J=7.8 Hz, 1H), 7.40-7.34 (m, 1H), 7.26 (d, J=9.0 Hz, 1H), 7.12 (s, 1H), 6.23 (s, 2H), 5.29 (s, 2H). Anal. Calcd for C19H13ClN6O.1.5H2O: C, 56.23; H, 4.47; N, 20.71%. Found C, 56.55; H, 4.45; N, 20.42%.