Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pt](=O)=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)nc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc(Cl)cc2)nc1
Yield: 94.2 %

Procedure:
4-Chlorophenoxy-5-nitropyridine (19.9 g) and platinum dioxide (0.1 g) were suspended in a mixture of tetrahydrofuran (100 ml) and ethyl acetate (50 ml), and catalytic reduction was carried out until 5.0 liters of hydrogen were absorbed. After removal of the catalyst by filtration, the solvent was distilled out under reduced pressure. The precipitated crystals were washed with a small amount of ether to give 16.5 g of 4-chlorophenoxy-5-aminopyridine as white crystals. M.P., 87°-88° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([OH:13])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(N(CC)CC)C>ClCCl>[Si:16]([O:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:12]=[CH:11]2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc2ccc(C(F)(F)F)nc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C(F)(F)F)nc12
Yield: 101.3 %

Procedure:
A solution of 2-trifluoromethylquinolin-8-ol (11.5 g), tert-butyldimethylsilyl chloride (8.9 g) and triethylamine (6.5 g) in dichloromethane (60 ml) was stirred overnight at room temperature. The reaction mixture was washed with water (2×50 ml), dried over sodium sulfate, filtered and the solvent removed in vacuo to give the product (17.9 g) as a white solid
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[CH2:32][C@@H:19]4[O:20]C(C5C=CC(OC)=CC=5)[O:22][CH2:23][C@@H:18]4[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.COC1C=C(OC)C=CC=1CN.CC(O)=O>O.C1COCC1>[NH2:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[CH2:32][C@H:19]([OH:20])[C@H:18]([CH2:23][OH:22])[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(NCc6ccc(OC)cc6OC)ncnc54)C[C@@H]3O2)cc1
Agent: COc1ccc(CN)c(OC)c1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1ncnc2c1ccn2[C@@H]1C[C@@H](CO)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (123 mg, 0.238 mmol, prepared following the procedure described in Example 1a-f using 2,4-dimethoxybenzylamine in step c) and AcOH (1.00 mL, 17.6 mmol) in water (0.500 mL) and THF (0.500 mL) were stirred at rt overnight. The reaction mixture was concentrated in vacuo and purification by silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM afforded the title compound (43.0 mg, 73%). LC/MS: Rt=0.15 min, ES+ 249 (FA standard).
Reaction SMILES: CC([O:4][C@@H:5]1[C@H:9]2[O:10][CH2:11][C@@H:12]([OH:13])[C@H:8]2[O:7][CH2:6]1)=O.[N+:14]([O-])([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.C(OC(=O)C)(=O)C.CO>[CH2:11]1[O:10][C@@H:9]2[C@H:5]([O:4][N+:14]([O-:16])=[O:15])[CH2:6][O:7][C@@H:8]2[C@H:12]1[OH:13]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O

Procedure:
For this isosorbide-2-acetate is for example firstly nitrated with nitric acid in glacial acetic acid or acetic acid anhydride and subsequently the acetate group is cleaved off with potassium carbonate in methanol. In this process isosorbide-5-nitrate is obtained in an isomerically pure form and in excellent yield (FIG. 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[CH3:39][O:40][C:41]([C:43]1([NH2:52])[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42]>CN(C=O)C>[CH3:39][O:40][C:41]([C:43]1([NH:52][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([F:13])[C:10]([O:11][CH3:12])=[C:2]([Br:1])[CH:3]=2)[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: COc1c(F)cc(C(=O)O)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2cc(F)c(OC)c(Br)c2)Cc2ccccc2C1
Reaction time: 8 h
Yield: 88.4 %

Procedure:
2.4 g (9.64 mmol) of the compound of step 3 were dissolved in 40 ml of DMF and 2.49 g (19.27 mmol) of EDIA and 4.03 g (10.60 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate were added. Then a solution of 2.19 g (9.64 mmol) of 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in 10 ml of DMF was added. After stirring overnight, the mixture was evaporated to dryness and the residue purified by preparative RP HPLC (water/ACN gradient). 3.6 g of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH:12]([NH:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22])[CH3:13].CC1C=CC=C(C)[C:25]=1[NH2:26].BrCCC(Br)C.Cl>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:10][CH2:11][CH:12]([CH3:13])[N:14]([C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:22])[C:25]1=[NH:26]
Reactant: Cc1cccc(C)c1N
Reactant: Cc1cccc(C)c1NCCC(C)Nc1c(C)cccc1C
Agent: CC(Br)CCBr
Agent: Cl
Product: Cc1cccc(C)c1N1CCC(C)N(c2c(C)cccc2C)C1=N
Yield: 45.6 %

Procedure:
1,3-Bis(2',6'-dimethylphenyl-amino)-butane, applied as starting substance, can be prepared e.g. by the method of Shapiro et al. (loc. cit.), utilizing 2,6-dimethylaniline and 1,3-dibromobutane as starting materials. The free base boils at 159°-160° C./0.1 mm Hg, and the hydrochloride melts at 178°-180° C. Yield: 45.6%.
Reaction SMILES: [F:1][C:2]1([F:34])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]([C:22]3[C:30]4[C:25](=[C:26]([CH2:31][S:32][CH3:33])[CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH:12]3C(=O)O[C:15](C)([CH3:19])[O:14][C:13]3=[O:21])=[CH:10][C:4]=2[O:3]1>N1C=CC=CC=1.C(O)C.[Cu]>[F:34][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]([C:22]3[C:30]4[C:25](=[C:26]([CH2:31][S:32][CH3:33])[CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:12][C:13]([O:14][CH2:15][CH3:19])=[O:21])=[CH:10][C:4]=2[O:3]1
Reactant: CSCc1cccc2c(C(c3ccc4c(c3)OC(F)(F)O4)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(c1ccc2c(c1)OC(F)(F)O2)c1c[nH]c2c(CSC)cccc12

Procedure:
17 mg (271 μmol) of copper powder were added to a solution of 2.66 g (5.43 mmol) of the compound from Example 97A in 10 ml of pyridine and 2 ml of ethanol. The reaction mixture was heated under reflux for 4 h. It was concentrated, and the crude product was purified firstly by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) and then by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.73 g (74% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][N:17]=[N:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nnn[nH]2)CC1
Temperature: 100 °C
Reaction time: 20 h
Yield: 59.6 %

Procedure:
A mixture of 2.10 g (10.0 mmol) of 1-(t-butoxycarbonyl)-4-cyanopiperidine (from Step A), 1.95 g (30.0 mmol) of sodium azide and 1.60 g (30.0 mmol) of ammonium chloride in 20 mL of DMF was stirred at 100 ° C. for 20 h. The mixture was cooled and partitioned between 200 mL of methylene chloride and 200 mL of 1.0 N HCl and the layers were separated. The organic layer was washed with 200 mL of water, dried over magnesium sulfate and concentrated. Flash chromatography on 50 g of silica gel using 4:1 v/v methylene chloride/ethyl acetate+1% acetic acid, then 2:1 v/v methylene chloride/ethyl acetate+1% acetic acid as the eluent afforded 1.51 g (60%) of the title compound:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][CH2:39][N:40]5[CH:44]=[N:43][CH:42]=[N:41]5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][CH2:39][N:40]5[CH:44]=[N:43][CH:42]=[N:41]5)=[O:54])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCCn4cncn4)cc2)CCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)CCn4cncn4)cc2)CCN3CCC)cc1
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[2-(1,2,4-triazol-1-yl)ethyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.86 g) was dissolved in methylene chloride (25.8 ml), and to the mixture was added dropwise a solution of m-chloroperbenzoic acid (0.36 g) in methylene chloride (17.2 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[2-(1,2,4-triazol-1-yl)ethyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 284) (0.57 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:38]#[N:39])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:36])[C:15]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([C:22](=[O:35])[N:23]([CH3:34])[N:24]4C(OC(C)(C)C)=O)=[CH:20][CH:19]=3)=[O:16])[C:10](=[O:37])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:38]#[N:39])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:36])[C:15]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([C:22](=[O:35])[N:23]([CH3:34])[NH:24]4)=[CH:20][CH:19]=3)=[O:16])[C:10](=[O:37])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)Nc1ccc2c(=O)n(C)n(C(=O)OC(C)(C)C)c2c1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc2c(=O)n(C)[nH]c2c1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
75 mg (0.14 mmol) of tert-butyl 6-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (racemate) (Example 2.7A) were hydrolysed with TFA according to General Method 2. Yield: 37 mg (60% of theory)
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][N:4]1[C:12]([CH3:13])=[N:11][C:10]2[C:5]1=[N:6][C:7]([C:14]#[N:15])=[N:8][CH:9]=2.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:13][C:12]1[N:4]([CH2:3][C:2]([CH3:17])([CH3:16])[CH3:1])[C:5]2[C:10]([N:11]=1)=[CH:9][N:8]=[C:7]([C:14]#[N:15])[N:6]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cnc(C#N)nc2n1CC(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)Cn1c(CBr)nc2cnc(C#N)nc21

Procedure:
A mixture of 1.1 g 9-(2,2-dimethyl-propyl)-8-methyl-9H-purine-2-carbonitrile, 1.7 g of N-bromosuccinimide and 116 mg dibenzoylperoxide was heated for 18 hours under reflux in 5 ml of CCl4. The mixture was evaporated and the residue was chromatographed on silicagel using hexanes/ethylacetate yielding 8-bromomethyl-9-(2,2-dimethyl-propyl)-9H-purine-2-carbonitrile as pale yellow wax.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20]C1(C)OC(=O)CC(=O)O1.N1C=CC=CC=1>C(Cl)Cl.O=S(Cl)Cl.CS(C)=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17](=[O:19])[CH3:20])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
5.0 g (19.0 mmol) piperidine-1,4-dicarboxylic acid monobenzyl ester were dissolved in 200 ml DCM and 4.16 ml SOCl2. After heating 2 h to reflux the volatile components were removed under reduced pressure. The residue was dissolved in 200 ml DCM and 3.29 g (22.8 mmol) 2,2-dimethyl-[1,3]dioxane-4,6-dione as well as 4.6 ml (57 mmol) pyridine were added. The reaction mixture was stirred at room temperature over night, washed twice with 1 N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure to be subsequently submitted to column chromatography on silica gel with n-hexane/ethyl acetate to yield a product, which was dissolved in 50 ml DMSO/water (95:5) and heated to 70° C. for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate, washed twice with 0.1 N aqueous HCl, saturated aqueous Na2CO3 and brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using n-hexane/ethyl acetate as eluents to yield ketone (21).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[CH:2]=[CH2:3].Cl.[C:17](=O)(O)[O-].[Na+]>CO>[CH3:17][O:14][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH:2]=[CH2:3]
Reactant: C=CCc1ccccc1N[C@@H](C)C(=O)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCc1ccccc1N[C@@H](C)C(=O)OC

Procedure:
A solution of 0.06 mol of N-(2-allylphenyl)alanine, prepared as described by A. Padwa, H. L. Gingrich, and R. Lim in J. Org. Chem., 1982, 47, 2447-2456, and 0.066 mol of HCl in 100 mL of CH3OH is stirred at reflux for 8 hours. The solution is then cooled and treated with 0.066 molof sodium bicarbonate. The solvent is removed by rotary evaporator, and theresidue is dissolved in diethyl ether, filtered, dried over MgSO4, andfiltered. The solvent is removed by rotary evaporator to give N-(2-allylphenyl)alanine methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:5][C:6](=[O:19])[C@H:7]([CH2:15][C:16](=[O:18])[OH:17])[NH:8]C(=O)CC(C)=O.C1(C)C=CC=CC=1.[ClH:35].N[OH:37]>O.C(O)(=O)C>[OH2:2].[OH2:37].[ClH:35].[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH:5][C:6](=[O:19])[C@H:7]([CH2:15][C:16](=[O:17])[OH:18])[NH2:8]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CC(C)=O
Reactant: NO
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Reaction time: 2.5 h

Procedure:
The crude N-acetoacetyl-L-aspartyl-L-phenylalanine methyl ester was dissolved in 100 parts by volume of water and 11.7 parts by volume of acetic acid. Toluene, 200 parts by volume, and hydroxylamine hydrochloride, 6.95 parts by volume, were added and the mixture stirred for 2.5 hours. The aqueous layer was separated and cooled to 0°-5° C. 15 parts by volume concentrated hydrochloric acid were added and the resulting mixture was cooled at 0°-5° C. overnight. The precipitate was collected on a filter and air dried for 3 hours to give 26.4 parts of α-L-aspartyl-L-phenylalanine methyl ester hydrochloride dihydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5](Cl)[C:3]=1[NH2:4].[N+](C1C=CC(N)=CC=1)([O-])=O.Cl>O.[N+]([O-])(O)=O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: Nc1ccc([N+](=O)[O-])cc1
Solvent: O=[N+]([O-])O
Solvent: O
Product: Nc1ccc([N+](=O)[O-])cc1Cl
Yield: 90 %

Procedure:
A process for the preparation of substantially pure 2,6-dichloro-4nitroaniline by chlorinatin of 4-nitroaniline with chloring bleaching liquor in water using acids, which comprises chlorinating 1 mole of 4-nitroaniline in 3-6 mole of hydrochloric acid (HCl) or nitric acid (HNO3) in the form of a dilute, aqueous acid in the presence of a dispersing agent which is stable under the reaction conditions, the chlorination initially being carried out at 5° to 10° C. and then at 15°-20° C. and, finally, after 90-95% of the 2-chloro-4-nitroaniline intermediately formed has been converted into 2,6-dichloro-4-nitroaniline, the temperature of the aqueous suspension being increased from 15°-20° C. to 70° C., without further addition of chlorine bleaching liquor, and then by post-chlorinating, by renewed addition of chlorine bleaching liquor, at temperatures between 20 ° and 70° C., bringing the pH of the aqueous sispension to 9.0 and filtering off the 2,6-dichloro-4-nitroaniline formed and washing it with dilute mineral acid to provide 2,6-dichloro-4-nitroaniline of a purity of 96% or above, and a melting point of 187°-191° C. and in a yield of 80% or above.
Reaction SMILES: [CH:1](/[C:9]1[N:10]=[C:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][C:14]3[N:22]=[CH:23][CH:24]=[CH:25][C:13]=3[N:12]2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([C:33]2([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1.CO.[Pd]>[C:3]1([CH2:2][CH2:1][C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]4[N:22]=[CH:23][CH:24]=[CH:25][C:13]=4[N:12]3[C:26]=2[C:27]2[CH:28]=[CH:29][C:30]([C:33]3([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])[CH2:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(/C=C/c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CCc4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1

Procedure:
(E)-tert-butyl (1-(4-(2-styryl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate was stirred in THF-MeOH under hydrogen in the presence of 5% Pd/C to give the title compound 1HNMR (CDCl3) 400 MHz δ: 8.10 (dd, J=7.7, 1.4 Hz, 1H), 7.99 (dd, J=4.6, 1.2 Hz, 1H), 7.34-7.27 (m, 3H), 7.24 (d, J=6.9 Hz, 1H), 7.18 (d, J=7.5 Hz, 2H), 7.14 (td, J=7.5, 1.2 Hz, 1H), 6.95 (d, J=7.5 Hz, 1H), 6.90 (d, J=7.5 Hz, 2H), 6.78 (d, J=7.5 Hz, 1H), 6.59 (dd, J=8.0, 4.6 Hz, 1H), 6.29 (s, 1H), 5.08 (s, 1H), 3.12-3.07 (m, 2H), 3.01-2.95 (m, 2H), 2.56-2.38 (m, 4H), 2.16-2.07 (m, 1H), 1.91-1.82 (m, 1H), 1.48-1.19 (m, 9H); LC/MS [M+H]: 584.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:53]=[O:54])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:55]=[O:56].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][C:49]([F:51])([F:52])[F:50])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:55][OH:56])[CH:53]=[O:54])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 70 °C
Reaction time: 25 h

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 71 (1.06 g, 1.39 mmol) was dissolved in 20 mL 1,4-dioxane, followed by addition of 2.3 mL 37% formaldehyde solution and 4 mL 2.9 M sodium hydroxide. The reaction mixture was stirred for 25 hours at 70° C. Thereafter, the reaction mixture was concentrated under reduced pressure before 20 mL water and 10 mL saturated sodium chloride solution were added. The reaction mixture was extracted with ethyl acetate (30 mL×3). The organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]-methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 7j (1.1 g, yellow grease), which was used directly in the next step without purification.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:26][C:27]1[C:32]([C:33]#[N:34])=[CH:31][N:30]=[CH:29][N:28]=1>>[C:33]([C:32]1[C:27]([NH:26][C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=[N:28][CH:29]=[N:30][CH:31]=1)#[N:34]
Reactant: N#Cc1cncnc1N
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Product: CCc1cc2c(C(=O)Nc3ncncc3C#N)cnc(OC)c2o1
Yield: 58.2 %

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (200 mg) and 4-aminopyrimidine-5-carbonitrile (84 mg). Purification by trituration with ethyl acetate and methanol gave the title compound (110 mg) as an off white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22](Cl)[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1)[CH3:11].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([SH:36])=[CH:32][CH:31]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([S:36][C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: COc1ccc(S)cc1
Reactant: COC(=O)C(Cl)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Sc1ccc(OC)cc1

Procedure:
The title compound was prepared as a gum from methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-chloropropanoate and 4-methoxythiophenol by a procedure similar to that described in Example 23.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[F-].[K+].[N+](C1C=C(S(O[CH2:26][C@H:27]2[CH2:29][O:28]2)(=O)=O)C=CC=1)([O-])=O>C1COCC1>[O:28]1[CH2:29][C@@H:27]1[CH2:26][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: c1ccc2c(c1)CCNC2
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCN(C[C@H]1CO1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 1,2,3,4-tetrahydroisoquinoline (5 g, 7.52 mmol) in THF (100 mL) was added KF (8.57 g, 150.4 mmol) at 0° C. (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (10.7 g, 41.4 mmol) was added to the reaction in 1 h. The solution was stirred at room temperature overnight. The solid was removed by filtration and washed with THF. The solution was then concentrated and the residue used for next step without further purification (11.3 g Yield 80%). LCMS (m/z): 190.1 (M+1).