Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([C@H:23]2[CH2:28][CH2:27][C@@H:26]([NH:29]C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:14]1([CH2:13][CH2:12][CH2:11][CH:10]([NH:20][C:21]([C@H:23]2[CH2:24][CH2:25][C@@H:26]([NH2:29])[CH2:27][CH2:28]2)=[O:22])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@@H](C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N-(tert-Butoxycarbonyl)-cis-4-amino-1-cyclohexanecarboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (24) (1.80 g; 3.65 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (15 mL) is added in a slow stream, and the solution is stirred for 6 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product. CIMS: MH+ 393
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[CH2:27][CH2:28][N:20]([C:21]=34)[C:19]3[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:18]=3[N:17]=2)[CH2:12][CH2:11]1.ClCCl>CN(C)C=O>[Br:1][C:30]1[C:31]([CH3:33])=[CH:32][C:18]2[N:17]=[C:16]([N:13]3[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH2:14]3)[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[CH2:27][CH2:28][N:20]([C:21]=34)[C:19]=2[CH:29]=1
Reactant: Cc1ccc2c(c1)N=C(N1CCN(C)CC1)c1cccc3c1N2CC3
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc2c(cc1Br)N1CCc3cccc(c31)C(N1CCN(C)CC1)=N2
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
A solution of N-bromosuccinimide (0.91 g, 5.1 mmoles) in dimethylformamide (3 ml) was added dropwise to a solution of 6-(4-methyl-1-piperazinyl)-9-methyl-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (1.6 g, 4.8 mmoles) in dimethylformamide (30 ml) at 0°-3° C. The reaction mixture was stirred for 30 minutes. The solution was poured into dichloromethane (250 ml), and was washed with brine (4 times, 150 ml), and dried over anhydrous magnesium sulfate. The solvent was removed at reduced pressure and the residue was dried. Purification was accomplished by flash chromatography on an aluminium oxide column (grade III, 60 g), eluted with dichloromethane (500 ml) and 2% methanol in dichloromethane (250 ml). The fractions containing the product were pooled and concentrated. Recrystallization from 2-propanol:water (1:1, 20 ml) yielded 230 mg (11.6%) of product, mp 177°-177° C.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[C:27](=[O:28])[N:6]2[C:7]([C:24]([O-:26])=[O:25])=[C:8]([CH2:11][N+:12]([CH3:23])([CH3:22])[CH2:13][C:14]3[NH:15][CH:16]=[C:17]([OH:21])[C:18](=[O:20])[CH:19]=3)[CH2:9][S:10][C@H:5]12.C[Si](C)(C)NC(=O)C.CS([O:41][C:42](=O)[C:43]([C:52]1[N:56]=[C:55]([NH2:57])[S:54][N:53]=1)=[N:44][O:45][C:46]([C:49]([OH:51])=[O:50])([CH3:48])[CH3:47])(=O)=O.C(OCC)(=O)C>O1CCCC1>[NH2:57][C:55]1[S:54][N:53]=[C:52]([C:43](=[N:44][O:45][C:46]([C:49]([OH:51])=[O:50])([CH3:48])[CH3:47])[C:42]([NH:3][C@@H:4]2[C:27](=[O:28])[N:6]3[C:7]([C:24]([O-:26])=[O:25])=[C:8]([CH2:11][N+:12]([CH3:23])([CH3:22])[CH2:13][C:14]4[NH:15][CH:16]=[C:17]([OH:21])[C:18](=[O:20])[CH:19]=4)[CH2:9][S:10][C@H:5]23)=[O:41])[N:56]=1
Reactant: CC(C)(ON=C(C(=O)OS(C)(=O)=O)c1nsc(N)n1)C(=O)O
Reactant: C[N+](C)(CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1)Cc1cc(=O)c(O)c[nH]1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+](C)(C)Cc3cc(=O)c(O)c[nH]3)CS[C@H]12)c1nsc(N)n1)C(=O)O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
7β-Amino-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4-carboxylate dihydrochloride (181 mg) was suspended in tetrahydrofuran (9.1 ml). To the suspension was added N-(trimethylsilyl)acetamide (788 mg), and the mixture was stirred at 35° C. for 30 minutes and cooled to 5° C. To the resulting solution was added a solution of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetic methanesulfonic anhydride (syn isomer) (169 mg) in tetrahydrofuran (0.5 ml). The mixture was warmed to 20° C. and stirred for 1.2 hours. The mixture was poured into ethyl acetate (200 ml) and the resulting precipitates were collected by filtration, washed with ethyl acetate and diisopropyl ether and dried in vacuo. The powder was suspended in water (40 ml) and adjusted to pH 1 with 1N hydrochloric acid. After the insoluble materials were removed by filtration, the filtrate was chromatographed on Diaion HP-20 (15 ml) and the elution was carried out with 15% aqueous isopropyl alcohol. The eluate was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4-carboxylate (syn isomer) (120 mg).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:36])[CH:15]=[CH:16][CH:17]2[C:22]([CH3:24])([CH3:23])[C:21]([CH3:25])=[C:20]([C:26]([O:28]C(C)(C)C)=[O:27])[C:19]([CH3:33])=[C:18]2[O:34][CH3:35])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].BrC(C)(C)C(OC(C)(C)C)=O>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14](=[O:36])[CH:15]=[CH:16][CH:17]2[C:22]([CH3:23])([CH3:24])[C:21]([CH3:25])=[C:20]([C:26]([OH:28])=[O:27])[C:19]([CH3:33])=[C:18]2[O:34][CH3:35])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(C(=O)C=CC2C(OC)=C(C)C(C(=O)OC(C)(C)C)=C(C)C2(C)C)cc1
Agent: CC(C)(C)OC(=O)C(C)(C)Br
Product: CCCCCCCc1ccc(C(=O)C=CC2C(OC)=C(C)C(C(=O)O)=C(C)C2(C)C)cc1

Procedure:
This compound was synthesized from 1-[4-heptylphenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl]prop-2-en-1-one (compound 38) and tert-butyl bromoisobutyrate according to general method 4 described earlier.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[N:16]=[CH:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=[O:33].CO>[Pd]>[CH:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[N:16]=[CH:15]2)[CH2:12][CH2:13]1)=[O:33]
Reactant: O=CO
Reactant: Fc1ccc(-c2ncn(C3CCN(Cc4ccccc4)CC3)c2-c2ccncc2)cc1
Agent: [Pd]
Solvent: CO
Product: O=CN1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccncc2)CC1
Temperature: 25 °C

Procedure:
1-(1-Benzylpiperidin-4-yl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole (100 mg; prepared in Example 40) was dissolved in 10% formic acid/methanol under argon and palladium black (100 mg) mixed in 10% formic acid/methanol was added. The reaction was stirred under argon at room temperature for sixteen hours. The reaction mixture was evaporated and the residue mixed in H2O/ethyl acetate and the pH taken to 10. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic layers were evaporated and the residue was flash chromatographed (silica gel/methylene chloride/methanol) to yield the title compound, an off-white solid. ES (+) MS m/e=351 (MH+)
Reaction SMILES: [CH3:1][N:2]([C@@H:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:24][CH3:25])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4].Cl>CCOCC.O1CCOCC1>[CH3:1][N:2]([C@@H:23]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:24][CH3:25])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4]
Reactant: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1,1-Dimethylethyl 4-[4-[[methyl[(1R)-1-phenylpropyl]amino]carbonyl]-2-thiazolyl]-1-piperidinecarboxylate (i.e. the product of Example 1, Step D) (3.6 g, 8.1 mmol) was dissolved in 100 mL of ether and treated with 20 mL of 4 N HCl in dioxane. The reaction mixture was stirred at ambient temperature for 4 h during which time a precipitate formed and was collected. The mother liquid was concentrated under reduced pressure, treated with 20 mL of 4 N HCl in dioxane, stirred at ambient temperature for 1 h and concentrated under reduced pressure. The residue was combined with the previously collected precipitate, dissolved in water and washed with ether. The aqueous layer was basified with 1 N aqueous NaOH solution and extracted with ethyl acetate. The extract was dried over MgSO4 and concentrated under reduced pressure to give 2.33 g of the title compound as an orange oil suitable for use in subsequent reactions.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
2-Fluoronitrobenzene (1.5 g) and 4-chlorophenol (1.3 g) were dissolved in dimethylformamide (20 ml) and potassium carbonate (1.4 g) was added thereto. The mixture was stirred overnight at 80° C. After the mixture was cooled, water (100 ml) was added thereto and the mixture was extracted with ethyl acetate (50 ml×2). The mixture was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was re-crystallized from methanol, to thereby yield the target compound (2.2 g) as pale-yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:26]C1C(=O)C(C)(C)C(Br)C1=O>C1COCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17]([Br:26])[CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2ccc3c(N)ncnn23)c1
Reactant: CC1(C)C(=O)C(Br)C(=O)C1Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cccc(-c2cc(Br)c3c(N)ncnn23)c1
Temperature: -20 °C
Reaction time: 2 h
Yield: 146.4 %

Procedure:
To a solution of [3-(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzyl]-carbamic acid tert-butyl ester (3.3 g, 9.7 mmol) in THF (73 mL) cooled to −20° C. (isopropanol/ice/CO2), 2,5-dibromo-4,4-dimethyl-cyclopentane-1,3-dione (1.4 g, 4.9 mmol) was added in four portions over 15 mins. The mixture was allowed to stir at −20° C. for 2 hours. The mixture was quenched with sodium thiosulfate solution (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water, brine, dried by Na2SO4, filtered and concentrated. The residue was purified by Biatage® to give desired product 3 g (72%). NMR (300 MHz, DMSO-d5) δ 7.80-7.7 (m, 3 H), 7.5 (m, 2 H), 7.2 (m, 2 H), 4.0 (m, 2 H), 1.5 (s, 9 H); ES-MS m/z 420 [M+H]+, HPLC RT (min) 2.91.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7](I)=[N:6]1.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC.[NH2:45][C:46]1[C:51]([NH2:52])=[N:50][C:49](Br)=[CH:48][N:47]=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:48]2[N:47]=[C:46]([NH2:45])[C:51]([NH2:52])=[N:50][CH:49]=2)=[N:6]1
Reactant: Nc1ncc(Br)nc1N
Reactant: Fc1ccccc1Cn1nc(I)c2cccnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)CCCC
Solvent: C1COCCO1
Product: Nc1ncc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C

Procedure:
Under argon, 425 mg (1.20 mmol) of the compound from Example 33A were initially charged in 1,4-dioxane (11 ml), and the reaction mixture was purged with argon for 10 min. Thereafter, 0.91 ml (1.80 mmol) of hexabutylditin and 250 mg (1.32 mmol) of 2,3-diamino-5-bromopyrazine were added. Subsequently, 422 mg (0.60 mmol) of bis(triphenylphosphine)palladium(II) chloride were added and the reaction mixture was heated to reflux overnight. Thereafter, the mixture was cooled to RT and filtered through Celite, and the filtrate was concentrated. The residue was admixed with methanol, and the solids were filtered off and discarded. The filtrate was taken up in methanol-dichloromethane, absorbed onto diatomaceous earth and purified on silica gel (eluent: cyclohexane-ethyl acetate 2:1, 1:1). This gave 151 mg (31% purity, 11% of theory) of the title compound. The crude product was converted further without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[CH:20]([CH:22]=[CH2:23])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:15]([C:12]([CH2:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])([CH2:21]/[CH:20]=[CH:22]/[CH3:23])[CH:13]=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: C=CC(C)O
Reactant: CCCCC(C=O)CS(=O)(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C/C=C/CC(C=O)(CCCC)CS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a stirred solution of 2-(((4-chlorophenyl)-sulfonyl)methyl)hexanal (3.38 g, 11.73 mmol) in 30 ml of toluene in a RBF fitted with a Dean-Stark trap is added 2-hydroxy-3-butene (5 mL, 57.73 mmol), followed by p-toluenesulfonic acid (0.13 g) at room temperature under nitrogen. The mixture is heated to reflux for 20 hours. After cooling to room temperature, the toluene solution is diluted with 10 mL of ethyl acetate and washed with 10 mL of saturated NaHCO3 solution. The aqueous phase is extracted with ethyl acetate. The combined organic extract is washed with water (2×10 mL), brine (1×10 mL), and dried with MgSO4. After removing solvents, the product is obtained as a brownish oil in 98% yield.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[NH:15]1>>[CH3:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[N:15]1[C@H:14]([CH3:13])[CH2:18][O:17][C:16]1=[O:19])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: COC(=O)c1ccc(N2C(=O)OC[C@H]2C)c(C)c1
Yield: 100.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using methyl 4-bromo-3-methylbenzoate (1.1 g) and (R)-4-methyloxazolidin-2-one (607 mg) described in Preparation Example 25, the title compound (1.2 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([C:21](=[O:23])[CH3:22])[C:5]([OH:20])=[C:6]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]=1[O:8][CH3:9].[Br:25][CH2:26][CH2:27]Br>>[Br:25][CH2:26][CH2:27][O:20][C:5]1[C:6]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[C:3]([CH3:24])[C:4]=1[C:21](=[O:23])[CH3:22]
Reactant: BrCCBr
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(O)c1OCCCc1ccccc1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCCc1ccccc1
Yield: 100 %

Procedure:
Example 34a (4.3 g, 17 mmol) was reacted with 1,2-dibromoethane (40 mL) as described under General Procedure F to afford the title compound (5.5 g, 100%) as a red oil. 1H NMR (300 MHz, CDCl3) δ 7.33-7.18 (m, 5H), 4.30 (t, J=6.3 Hz, 2H), 4.09 (t, J=6.3 Hz, 2H), 3.89 (s, 3H), 3.51 (t, J=6.0 Hz, 2H), 2.83 (t, J=8.1 Hz, 2H), 2.52 (s, 3H), 2.20 (s, 3H), 2.14-2.05 (m, 2H). MS (ES+) m/z 457 (M+H+).
Reaction SMILES: [NH3:1].C(O)C.[O:5]1[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6]1>O>[OH:5][CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][NH2:1]
Reactant: N
Reactant: CCCCCCC1CO1
Solvent: CCO
Solvent: O
Product: CCCCCCC(O)CN
Reaction time: 1.17 h
Yield: 76.6 %

Procedure:
One-thousand one-hundred grams of ammonia gas was introduced into a mixture of 6 liters of ethanol and 1 liter of water and within 30 minutes there were dropped in at room temperature 320 grams of 1,2-epoxyoctane. The mixture was left at room temperature for 70 minutes under gentle stirring, then the solvent and excess ammonia drawn off and the residue rectified in a vacuu. There were obtained 277.6 grams (77.1% of theory) of 2-hydroxyoctyl amine having a boiling point (0.4 mm Hg) of 80° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:31][CH3:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18](=O)[C:17]3[C:16]([C:27]([O:29]C)=O)=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11]2)=[CH:6][CH:5]=1.O.[NH2:34][NH2:35]>>[CH3:1][O:2][CH:3]([O:31][CH3:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[NH:11][C:12]3[C:17]4[C:18](=[N:34][NH:35][C:27](=[O:29])[C:16]=4[CH:15]=[CH:14][CH:13]=3)[CH:19]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1ccc(C(OC)OC)cc1)N2
Reactant: NN
Solvent: O
Product: COC(OC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To methyl 2-(4-(dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (120 mg, 0.28 mmol) was added hydrazine monohydrate (20 mL) and the mixture was stirred under 40° C. for 3 h. The resulting mixture was evaporated under reduced pressure to 10 ml and then filtered, 89 mg of solid of 8-(4-(dimethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one was obtained (yield: 78%). LC-MS (ESI) m/z: 414 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([OH:11])[CH2:7][C@H:6]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:4].[CH3:22][C:23]([Si:26](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])[CH3:24].N1C=CN=C1>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][Si:26]([C:23]([CH3:25])([CH3:24])[CH3:22])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:7][C@H:6]1[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:4]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1CC[C@@H](O)C[C@H]1C(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of compound 4 (10.9 mmol) in DMF (35 mL) were added TBDPSCl (24.0 mmol) and imidazole (32.7 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was then diluted with DCM (140 mL) and washed sequentially with 1N HCl (140 mL) and H2O (140 mL). Organics were dried, concentrated, and purified by silica gel chromatography (PE/EtOAc) to yield compound 5 as a colourless oil in 65% yield.
Reaction SMILES: [OH:1][C@@H:2]([CH3:7])[CH2:3][C:4]([O-:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][N:51]=[C:50]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)=[CH:57][CH:56]=3)[N:49]=2)=[CH:44][CH:43]=1>CN(C=O)C>[OH:1][C@@H:2]([CH3:7])[CH2:3][C:4]([NH:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][N:51]=[C:50]([NH:54][C:55]3[CH:56]=[CH:57][C:58]([N:61]4[CH2:62][CH2:63][O:64][CH2:65][CH2:66]4)=[CH:59][CH:60]=3)[N:49]=2)=[CH:44][CH:43]=1)=[O:6]
Reactant: C[C@H](O)CC(=O)[O-]
Reactant: Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](O)CC(=O)Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a solution of (S)-3-hydroxybutyrate (0.180 g, 1.73 mmol), HATU (0.602 g, 1.58 mmol), DIEA (1.0 mL, 5.4 mmol) in DMF (3.0 mL) was added a solution of 4-(4-aminophenyl)-N-(4-morpholinophenyl)pyrimidin-2-amine (0.500 g, 1.44 mmol) in DMF (1.0 mL). The reaction mixture was stirred at rt for 2 hours, at which time it was quenched with saturated NaHCO3 (10 mL, aq.), extracted into DCM (3×), and washed with brine (1×). The organic layers were dried with sodium sulfate and concentrated. The product was purified by reverse phase HPLC to afford (S)-3-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)butanamide (0.136 g, 22% yield) as a light brown solid. (363) 1H-NMR (400 MHz, DMSO-d6): 10.14 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.27 (d, 1H), 6.94 (d, 2H), 4.79 (d, 1H), 4.11 (m, 1H), 3.74 (m, 4H), 3.05 (m, 4H), 2.47 (dd, 1H), 2.35 (dd, 1H)), 1.15 (d, 3H); MS (EI) m/z for C24H28N5O3: 434.3 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[C@H:4]([F:35])[CH2:3]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:31]1([CH2:30][O:29][C:21]2[CH:22]=[CH:23][C:24]([CH:26]([F:28])[F:27])=[CH:25][C:20]=2[C:19]2[C:14]3[NH:13][C:12]([CH3:34])=[C:11]([C:9]([NH:8][C@@H:5]4[CH2:6][CH2:7][C@@H:2]([NH:1][C:36](=[O:39])[CH2:37][CH3:38])[CH2:3][C@H:4]4[F:35])=[O:10])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:32][CH2:33]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CC[C@@H](N)C[C@H]1F
Reactant: CCC(=O)Cl
Product: CCC(=O)N[C@@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)[C@H](F)C1

Procedure:
Starting from N-[(1R*,2R*,4R*)-4-amino-2-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f67) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([CH2:25][NH2:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([CH2:25][NH:26][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CN)ccc2c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CNS(C)(=O)=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.3 %

Procedure:
To a solution of crude tert-butyl[6-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.16 g) (Example 285) in tetrahydrofuran (2 mL) was added methanesulfonyl chloride (0.028 mL, 0.36 mmol) and triethylamine (0.050 mL, 0.36 mmol), and the mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water (4 mL) and concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1 (v/v)) to give tert-butyl(2-isobutyl-6-{[(methylsulfonyl)amino]methyl}-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.13 g, 84%) as a pale yellow oil.