Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]([OH:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1.C(Cl)(Cl)Cl.NC1C=C(OC2C=CC(C(O)C)=CC=2)C=CC=1N>C(O)C.O=[Mn]=O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(O)c1ccc(Oc2ccc3[nH]cnc3c2)cc1
Agent: O=[Mn]=O
Agent: CC(O)c1ccc(Oc2ccc(N)c(N)c2)cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc(Oc2ccc3[nH]cnc3c2)cc1

Procedure:
Crude 1-[4-(1H-benzimidazol-5-yloxy)phenyl]ethanol was dissolved in 75 mL of 1:1 ethanol:chloroform and stirred with MnO2 (1.4 g, 10 equivalents based on step 2 starting material) at 80 degrees Centigrade for approximately 18 hours. A second 1.4 g of MnO2 was added and the reaction was heated for an additional 24 hours. A third 1.4 g of MnO2 was added and the reaction was heated for an additional 24 hours. The reaction was filtered through celite and concentrated onto basic alumina. The crude product was purified by silica gel column chromatography to give 1-[4-(1H-benzimidazol-5-yloxy)phenyl]ethanone and an impurity that was carried forward to the next step. (M+1) 253.0, 1.41 min (LC/MS method B).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[CH2:7]2)[CH2:3][CH2:2]1.Cl[C:17]1[N:18]=[N:19][C:20]([C:23]2[S:27][N:26]=[C:25]([CH3:28])[N:24]=2)=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:28][C:25]1[N:24]=[C:23]([C:20]2[N:19]=[N:18][C:17]([N:1]3[CH2:6][CH2:5][C:4]4([C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[C:8](=[O:15])[CH2:7]4)[CH2:3][CH2:2]3)=[CH:22][CH:21]=2)[S:27][N:26]=1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: O=C1CC2(CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)CC(=O)c3ccccc34)nn2)n1

Procedure:
The object product (106 mg, 40%) was obtained in the same manner as in Example 1 and using spiro[indene-1,4′-piperidin]-3(2H)-one (190 mg), 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (150 mg) and potassium carbonate (150 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13].[CH3:14][Mg]Br>CCOCC>[OH:13][C:7]1([CH3:14])[C:8]2[C:3](=[C:2]([CH3:1])[CH:11]=[C:10]([CH3:12])[CH:9]=2)[CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(C)c2c(c1)C(=O)CCC2
Reactant: C[Mg]Br
Solvent: CCOCC
Product: Cc1cc(C)c2c(c1)C(C)(O)CCC2
Yield: 97 %

Procedure:
Following the procedure of Example 1, step 1, 25.20 g (0.145 ml) of 5,7-dimethyltetralone in 200 ml of anhydrous ether was reacted with 60.3 ml of 3.0M methyl magnesium bromide in ether to give 26.64 g (97%) of the title product as an orange oil. NMR δ(CDCl3) 1.56 (3H, s), 1.70 (1H, s), 1.78-2.04 (4H, m), 2.20 (3H, s), 2.30 (3H, s), 2.60 (2H, m), 6.90 (1H, s), 7.30 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:22][OH:23])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccc(-c2ccc(F)cc2)cc1
Yield: 92.6 %

Procedure:
A stirred mixture of 4-(4′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid (2.72 g, 0.0100 mol), hydroxylamine hydrochloride (0.848 g, 0.0122 mol) and sodium carbonate (1.304 g, 0.0123 mol) in absolute ethanol (60 mL) was refluxed for 22 hours and allowed to cool. The solids were filtered, washed with additional ethanol, and allowed to air dry overnight. The solids were dissolve din methanol-water, and the solution acidified with 1.0 M hydrochloric acid (10 mL, 0.010 mol HCl). The mixture was concentrated to approximately 30 mL on a rotary evaporator, and the resulting precipitate filtered and dried in vacuo to give 2.66 g of 4-(4′-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid as a pale yellow solid; mp 152-153° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][C:5]=1[Cl:11].N([O-])=[O:14].[Na+]>OS(O)(=O)=O.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:14])=[CH:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(O)cc1Cl

Procedure:
Compound of example 162 (7.9 g, 42.5 mmol) suspended in 10% aqueous H2SO4 (80 mL) was reacted with NaNO2 (3.5 g, 52.1 mmol in 35 mL water) as described in example 174. It was treated with a solution of CuSO4.5H2O (128 g, 513 mmol) and Cu2O (5.5 g, 38.4 mmol) in water (800 mL) as described in the same procedure to obtain the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[O:7])[CH2:3]1.[C:15](=[O:18])(O)[O-:16].[Na+].O>O1CCOCC1.O>[C:4]([O:16][C:15]([N:2]1[CH2:5][CH:4]([C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH2:3]1)=[O:18])([CH3:6])([CH3:5])[CH3:3]
Reactant: O=C([O-])O
Reactant: O=C(c1ccc(Cl)cc1)C1CNC1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C(=O)c2ccc(Cl)cc2)C1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
A solution of azetidin-3-yl-(4-chloro-phenyl)-methanone hydrochloride (50 g, 210 mmol) in dioxan:water 1:1 (800 ml) is added powdered sodium bicarbonate (61.7 g, 730 mmol) and the reaction mixture cooled to 10° C. Di-tbutyl-dicarbonate (52.6 g, 240 mmol) is added portion wise and the reaction mixture allowed to warm to room temperature with stirring for 1.5 hours. The reaction mixture is poured into water (1500 ml) and the resulting white precipitate filtered off and dried under vacuum to afford 3-(4-Chloro-benzoyl)-azetidine-1-carboxylic acid tert-butyl ester. 1H NMR 400 MHz, CDCl3, δ 1.45 (9H), 4.10 (1H), 4.20 (4H), 7.47 (2H), 7.80 (2H)
Reaction SMILES: [CH3:1][CH:2]([CH3:37])[C@H:3]([NH:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1)[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:5].Br[C:39]1[CH:44]=[CH:43][C:42]([C:45]2[NH:49][C:48]([C@@H:50]3[CH2:54][CH2:53][CH2:52][N:51]3[C:55](=[O:66])[C@@H:56]([NH:60][C:61]3[S:62][CH:63]=[CH:64][N:65]=3)[CH:57]([CH3:59])[CH3:58])=[N:47][CH:46]=2)=[CH:41][CH:40]=1.C([O-])(O)=O.[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]1([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[N:49]=[C:48]([C@@H:50]4[CH2:54][CH2:53][CH2:52][N:51]4[C:55](=[O:66])[C@@H:56]([NH:60][C:61]4[S:62][CH:63]=[CH:64][N:65]=4)[CH:57]([CH3:59])[CH3:58])[NH:47][CH:46]=3)=[CH:41][CH:40]=2)[CH:20]=[CH:21][C:16]([C:13]2[N:12]=[C:11]([C@@H:7]3[CH2:8][CH2:9][CH2:10][N:6]3[C:4](=[O:5])[C@@H:3]([NH:31][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[CH:2]([CH3:37])[CH3:1])[NH:15][CH:14]=2)=[CH:17][CH:18]=1
Reactant: CC(C)[C@H](Nc1nccs1)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: CC(C)[C@H](Nc1nccs1)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)[C@H](Nc1nccs1)C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](Nc5nccs5)C(C)C)n4)cc3)cc2)c[nH]1
Temperature: 80 °C
Yield: 1.7 %

Procedure:
A mixture of (S)-3-methyl-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-(thiazol-2-ylamino)butan-1-one (275 mg, 0.527 mmol), (S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-2-(thiazol-2-ylamino)butan-1-one (250 mg, 0.527 mmol), NaHCO3 (133 mg, 1.582 mmol) and Pd(Ph3P)4 (60.9 mg, 0.053 mmol) in DME (3 mL) and Water (1 mL) was degassed by passing a stream of N2 through the mixture. The vessel was sealed and the reaction was heated at 80° C. overnight. The reaction mixture was diluted with H2O and extracted with EtOAc containing ca. 5% MeOH (×3). The combined org layers were concentrated, dissolved in MeOH and loaded onto an MCX cartridge. The cartridge was washed with MeOH and then NH3 in MeOH (2M). The appropriate fractions were concentrated in vacuo and the residue was purified by prep HPLC (CH3CN—H2O—NH4OAc). The material was purified by column chromatography (biotage) eluting with 0 to 20% MeOH in EtOAc. Further purification by prep HPLC (CH3CN—H2O—NH4OAc) followed by lyophilization afforded the title compound as a colorless solid (6.9 mg, 2%).
Reaction SMILES: FC(F)(OC1C=CC(OC2C=CC(C[NH2:17])=CC=2)=CC=1)C(F)F.C(N(CC)CC)C.[Cl:30][C:31]1[C:32]([CH3:40])=[N:33][N:34]([CH3:39])[C:35]=1[C:36](Cl)=[O:37]>C1(C)C=CC=CC=1>[Cl:30][C:31]1[C:32]([CH3:40])=[N:33][N:34]([CH3:39])[C:35]=1[C:36]([NH2:17])=[O:37]
Reactant: NCc1ccc(Oc2ccc(OC(F)(F)C(F)F)cc2)cc1
Reactant: Cc1nn(C)c(C(=O)Cl)c1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(C(N)=O)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 233.5 %

Procedure:
To a stirred mixture of 4-[4-(1,1,2,2-tetrafluoroethoxy)phenoxy]benzylamine (359 mg, 1.14 mM), triethylamine (136 mg, 1.35 mM) and toluene (20 ml) was added dropwise a solution (10 ml) of 4-chloro-1,3-dimethylpyrazole-5-carbonyl chloride (200 mg, 1.04 mM) in toluene at 0°-10° C., and the mixture was stirred for 3 h at room temperature. The mixture was poured into ice water, and the mixture was extracted with toluene. The extract was washed with saturated sodium hydrogen carbonate solution, saturated ammonium chloride solution and brine, dried with magnesium sulfate, and concentrated in vacuo. The residue was chromatographed over silica gel to give N-{4-[1,1,2,2,-tetrafluoroethoxy)phenoxy]benzyl}-4-chloro-1,3-dimethylpyrazole-5-carboxamide (420 mg, 86%) as colorless crystals, m.p. 101.3° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.Cl.[CH:25]([N:28]1[CH2:33][CH2:32][CH:31]([CH:34]2[CH2:38][CH2:37][CH2:36][NH:35]2)[CH2:30][CH2:29]1)([CH3:27])[CH3:26]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:21]([N:20]1[C:16]([C:10]2[N:11]=[C:12]3[C:13]4[CH:14]=[CH:15][C:2]([N:35]5[CH2:36][CH2:37][CH2:38][CH:34]5[CH:31]5[CH2:30][CH2:29][N:28]([CH:25]([CH3:27])[CH3:26])[CH2:33][CH2:32]5)=[CH:3][C:4]=4[O:5][CH2:6][CH2:7][N:8]3[CH:9]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)N1CCC(C2CCCN2)CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)N1CCC(C2CCCN2c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CC1
Temperature: 110 °C
Reaction time: 2 h
Yield: 10.2 %

Procedure:
A mixture of 12-bromo-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (300 mg, 0.800 mmol), 1-isopropyl-4-(pyrrolidin-2-yl)piperidine hydrochloride (163 mg, 0.800 mmol), Pd(PtBu3)2 (20 mg, 0.040 mmol), Na2OtBu (232 mg, 2.40 mol) in toluene (2 mL) in a seal tube was degassed with N2 for three times. The resulting mixture was stirred at 110° C. for 120 min. After the completion of the reaction, the solid was filtered off via Celite. The filtrate was concentrated and purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give racemic 175 (40 mg, 10% yield). The (R) and (S) enantiomers were separated by chiral-HPLC (OD-H column, 10% IPA in hexane isocratic) to give 7.0 mg one enantiomer and 10 mg the other enantiomer.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[NH:16][CH2:17][CH:18]([CH3:20])[CH3:19].[OH-].[Na+].Cl>CO.O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:21])=[O:2])=[C:7]([NH:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)C=Cc1ccc(C(C)(C)C)cc1NCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)CNc1cc(C(C)(C)C)ccc1C=CC(=O)O
Reaction time: 12 h
Yield: 100 %

Procedure:
3-(4-tert-butyl-2-isobutylaminophenyl)acrylic acid methyl ester (0.08 mmol, 22.8 mg) and NaOH (0.39 mmol, 15.76 mg) were added in methanol and water. The reaction mixture was stirred for 12 hrs. The reaction mixture was acidified with 5% HCl solution. The reaction mixture was concentrated in vacuo to give a solid (22.02 mg, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[S:19])[CH:14]=[CH:15][NH:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]1[S:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([S:19][C:23]3[S:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)s1
Reactant: COc1cc2c(=S)cc[nH]c2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Sc3ccc([N+](=O)[O-])s3)ccnc2cc1OCc1ccccc1
Yield: 76.9 %

Procedure:
7-(Benzyloxy)-6-methoxy-1,4-dihydro-4-quinolinethione (14.3 g), 2-bromo-5-nitrothiophene (10 g), potassium carbonate (9.9 g) and dimethylformamide (150 ml) were stirred together at room temperature for 6 hours. Water was added, and the precipitated solid was filtered out and washed with water and then ethyl acetate to obtain 15.7 g of a yellow powder.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].[C:12]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)Cl>[C:15]([O:14][C:12]([N:19]1[CH2:22][CH:21]([NH:23][CH2:2][C:3]2[S:7][CH:6]=[N:5][C:4]=2[C:8]([O:10][CH3:11])=[O:9])[CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: COC(=O)c1ncsc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ncsc1CNC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A mixture of compound 3b (250 mg, 1.06 mmol), 1-Boc-3-aminoazetidine 1a (310 mg, 1.80 mmol), and K2CO3 (248 mg, 1.80 mmol) in THF (12 mL) was heated to reflux for 6 h. The reaction mixture was cooled to room temperature and diluted with CH2Cl2. The resulting solution was washed with aq. NaHCO3, dried over Na2SO4, and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH2Cl2) gave compound 3c (210 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[H-].[Na+].[C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20]Br)(=[O:15])[CH3:14].O>CN(C=O)C>[C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[Cl:1])(=[O:15])[CH3:14]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(=O)OCCOCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCOCn1cnc2c(Cl)ncnc21
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 6-chloropurine (6 g, 38.8 mmoles) in DMF was added sodium hydride 60% (0.93 g) over 1.5 hour period. (2-acetoxyethoxy)methyl bromide was then added at room temperature; the reaction mixture was allowed to stir for 2 hours under Nz atmosphere. H2O was added and the product was extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and evaporated in vacuo to give a light yellow solid 7.1 g, 68% yield of 9-[(2-acetoxy-ethoxy)methyl]-6-chloro-purine. The crude was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5](=[CH2:29])[CH2:6][C@H:7]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([CH3:29])[CH2:6][CH:7]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: [H][H]
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid ethyl ester (2-a, R1=Boc, R2=H, R3=CO2Et) is added to ethanol (5 ml) at ambient temperature. Triethylamine (170 μl) is then added to the mixture. 50 mg Palladium on carbon (10%, 50% water-wet, Degussa E101 NE/W) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is then stirred overnight at ambient temperature and pressure. The mixture is then filtered and concentrated under reduced pressure to afford 2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid ethyl ester (1-a, R1=Boc, R2=H, R3=CO2Et) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid ethyl ester (1-b, R1=Boc, R2=H, R3=CO2Et). Spectroscopic data as in Example 63. Ratio of diastereomers 70:30 (1-a, R1=Boc, R2=H, R3=CO2Et:1-b, R1=Boc, R2=H, R3=CO2Et) as determined by hplc (hplc method as in Example 65)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Li]CCCC.C[O:18][B:19](OC)[O:20]C.O>C(OCC)C>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([B:19]([OH:20])[OH:18])[CH:3]=1
Reactant: COB(OC)OC
Reactant: Brc1cnc2ccccc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: OB(O)c1cnc2ccccc2c1
Reaction time: 0.25 h
Yield: 92 %

Procedure:
A solution of 3-bromoquinoline (14.6 g (0.07 mole)) in 50 ml of diethylether was added at -40° under argon to a solution of 2 M n-BuLi (37.5 ml (0.075 mole) (in cyclohexane)) in 50 ml Et2O. The reaction mixture was stirred 15 minutes and 0.075 mole (7.8 g, 8.5 ml) trimethylborate was added rapidly over 2 minutes. The mixture was stirred 15 minutes at 0° C. and 4 ml of H2O was added and stirring continued for 30 minutes. The volatiles were evaporated in vacuo to a yellow tar resi-due. The residue was dissolved in 150 ml ethyl alcohol to which was added 4 ml of acetic acid and reflux-ed for 45 minutes. The volatiles were evaporated in vacuo to a yellow oily residue. The residue was stirred with 40 ml of ether to give a yellow solid which was filtered, washed with ether and dried to give 11.14 g of a solid. The solid was stirred in 100 ml of water and filtered to give 3.26 g of a solid after air drying. The crude product was used directly in the next step.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([CH:18]3[CH2:23][O:22][CH2:21][CH2:20][O:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].[CH3:29][O-:30].[Na+].C(Cl)(Cl)Cl>CO>[O:19]1[CH2:20][CH2:21][O:22][CH2:23][CH:18]1[C:17]1[C:11]2[S:10][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:26]=[CH:27][N:28]=[C:3]([CH2:2][O:30][CH3:29])[CH:4]=3)=[N:13][C:12]=2[C:14]([O:24][CH3:25])=[CH:15][CH:16]=1
Reactant: C[O-]
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COCc1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)ccn1

Procedure:
From (+)-2-chloromethyl-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with sodium methylate in methanol. [α]D20=+65.1° (c=0.55, CHCl3), ES-MS m/e (%): 416 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:12]([Cl:11])(=[O:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccc(Cl)cc1
Product: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
At 5-10° C., to stirred chlorosulfonic acid (200 mL) was added 4-chlorobenzoic acid (78 g, 0.5 mol). The reaction mixture was then brought up to 150˜160° C. for 5 hours. After being cooled down to room temperature, the reaction mixture was slowly poured onto a large amount of ice and extracted with ether. The combined organic extracts were washed with ice water and dried over anhydrous magnesium sulfate. Evaporation of solvents afforded 4-chloro-3-(chlorosulfonyl)benzoic acid as a solid (76 g), which was directly used in the next steps.
Reaction SMILES: C([Mg]Br)(C)C.C([Li])CCC.[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([F:25])[C:22](Br)=[CH:21][C:20]=1[F:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][O:38][C@H:37]([C:41](=[O:46])N(OC)C)[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>O1CCCC1.O>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][O:38][C@H:37]([C:41](=[O:46])[C:22]2[CH:21]=[C:20]([F:27])[C:19]([O:18][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:24][C:23]=2[F:25])[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CON(C)C(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Reactant: Fc1cc(OCc2ccccc2)c(F)cc1Br
Agent: CC(C)[Mg]Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@H](C(=O)c2cc(F)c(OCc3ccccc3)cc2F)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
To a solution of 33 mL of isopropylmagnesium bromide (1M in tetrahydrofuran) in tetrahydrofuran (120 mL) was added with cooling (max+3° C.) n-butyllithium (41 mL, 1.6M in hexane). The mixture was cooled to −78° C., 1-benzyloxy-4-bromo-2,5-difluoro-benzene (8.2 g, 27 mmol) was added and stirred for 1.5 hours at this temperature. (S)-2-(Methoxy-methyl-carbamoyl)-morpholine-4-carboxylic acid tert-butyl ester (7.5 g, 27 mmol) was added dropwise within 10 min at −75° C. Stirring at −78° C. continued for 1 h and the reaction mixture was than poured into water (600 mL). Organic material was partitioned into ethyl acetate (3×), organic phases were pooled, washed with brine and dried with MgSO4 before being concentrated in vacuo. The residue was then purified by column chromatography (heptane-ethyl acetate (2:1)/silica gel) to give 7.5 g of the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:3])[CH3:2].Cl.[OH:21][C:22]1[C:31]([N:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[N:16]=[C:15]([C:17]([N:26]2[CH2:25][CH2:24][C:23]3[C:28](=[CH:29][CH:30]=[C:31]([N:32]([CH3:34])[CH3:33])[C:22]=3[OH:21])[CH2:27]2)=[O:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCc1nc(C(=O)O)c2ccccc2n1
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Agent: Cl
Product: CC(=O)NCCc1nc(C(=O)N2CCc3c(ccc(N(C)C)c3O)C2)c2ccccc2n1
Yield: 9 %

Procedure:
Reaction of 2-(2-(acetamido)ethyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 77 (9% yield) as brown oil. 1H NMR (300 MHz, CD3OD) δ 1.86 and 1.88 (2s, 3H), 2.62 and 2.66 (2s, 6H), 2.79 and 3.03 (2t, 2H), 3.26-3.30 (m, 2H), 3.54 and 4.14 (2t, 2H), 3.73-3.82 (m, 2H), 4.41 and 4.99 (2s, 2H), 6.35 and 6.79 (2d, 1H), 6.91 and 7.10 (2d, 1H), 7.67-7.77 (m, 1H), 7.88-8.07 (m, 3H); MS (ESI) m/z 434 ([M+H]+).