Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:2].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)(Cl)Cl>[C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc(Br)cc1C(C)=O
Yield: 90.2 %

Procedure:
13.31 g of 2-acetyl-4-bromophenol, 11.0 g of ethyl bromoacetate and 9.7 g of anhydrous potassium carbonate were refluxed under heating in 70 ml of acetone for 2 hours. Insoluble materials were removed by filtration, and the resulting filtrate was concentrated and dried. The residue thus obtained was dissolved in chloroform, washed with water, and then dried to remove the solvent. The thus treated residue was washed with a mixed solvent system of ethanol and n-hexane to isolate insoluble crystals by filtration. In this way, 16.82 g of ethyl (2-acetyl-4-bromophenyl)oxyacetate was obtained in the form of colorless plate crystals.
Reaction SMILES: [CH2:1](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[C:40]([NH:57][C@H:58]([C:61]([OH:63])=[O:62])[CH2:59][SH:60])(=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55].C(Cl)(Cl)Cl>C(O)C.O>[C:40]([NH:57][C@H:58]([C:61]([OH:63])=[O:62])[CH2:59][S:60][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](CS)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCSC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(=O)O
Reaction time: 20 h

Procedure:
4.8 g of docosanyl-p-toluenesulfonate and 5 g of potassium carbonate are added to 3.6 g of N-palmitoyl-(L)-cysteine in 50 ml of ethanol. The mixture is heated under stirring and in a nitrogen atmosphere at 80° for 20 hours. After evaporating to dryness the residue is acidified with 1 N HCl so as to obtain a pH of about 3 and then it is distributed between chloroform and water. After having dried and evaporated the chloroform layer a colourless crystalline residue is obtained, which is recrystallized from ethyl acetate. There is thus obtained the N-palmitoyl-S-docosanyl-(L)-cysteine.
Reaction SMILES: [C:1]([SH:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]=[CH:7][CH2:8][CH2:9][CH:10]=[CH2:11]>>[C:1]([S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)S
Reactant: C=CCCC=C
Product: CC(C)(C)SCCCCCCSC(C)(C)C

Procedure:
The addition of tertiary-butyl mercaptan to 1,5-hexadiene according to the reaction:
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([NH2:10])=O)=[CH:6][C:5]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>O1CCCC1>[Br:1][C:2]1[C:7]([C:8](=[S:26])[NH2:10])=[CH:6][C:5]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:4][CH:3]=1
Reactant: CCNC(=O)Nc1cc(C(N)=O)c(Br)cn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Temperature: 70 °C
Reaction time: 18 h
Yield: 76.3 %

Procedure:
A suspended mixture of 5-bromo-2-(3-ethylureido)isonicotinamide (Intermediate 5, 237 g, 830 mmol), Lawesson's Reagent (336 g, 830 mmol), and tetrahydrofuran (3 L) was stirred at 70° C. for 18 h. The precipitate was collected by filtration and washed with methyl tert-butyl ether (2×500 L). This solid was then dried in the vacuum oven at 50° C. for 12 h to give 192 g (77%) of 5-bromo-2-(3-ethylureido)pyridine-4-carbothioamide as an off white solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](OCC)=[O:20]>>[CH3:13][O:12][C:10](=[O:11])[CH:9]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[C:19]([C:15]1[O:14][CH:18]=[CH:17][CH:16]=1)=[O:20]
Reactant: COC(=O)CC1CCCCC1
Reactant: CCOC(=O)c1ccco1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(C(=O)c1ccco1)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76.3 %

Procedure:
To an ice cold suspension of 0.92 g (23 mmol) of sodium hydride (NaH 60% dispersion in mineral oil) (previously washed with hexane and dried under vacuum) in 25 mL of 1,2-dimethoxyethane (DME) was added 0.9 g (5.76 mmol) of methyl cyclohexylacetate, and the resulting mixture was stirred at 0° C. for 20 min. Then 1.2 g (8.56 mmol) of ethyl 2-furoate was added, and the reaction mixture was heated at reflux overnight. The mixture was then cooled to 0° C., quenched by the addition of 1 M HCl solution to pH=3, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to give a brown oil which was chromatographed on silica gel (Biotage; 10% hexane in dichloromethane) to afford 1.1 g (76% yield) of desired 2-cyclohexyl-3-furan-2-yl-3-oxo-propionic acid methyl ester as indicated by 1H NMR.
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[NH2:14][OH:15]>CCO>[OH:15][NH:14][C:12](=[NH:13])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCC#N
Reactant: NO
Solvent: CCO
Product: CCCCCCCCCCCC(=N)NO
Temperature: 70 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
To a solution of undecyl cyanide (1.810 g, 9.98 mmol) in EtOH (20 mL) was added a 50% aqueous solution of hydroxylamine (1 mL) and the resulting reaction mixture was stirred at 70° C. for 48 h. The solvents were evaporated and the resulting white solid was dissolved in EtOAc (100 mL) and washed with H2O (2×20 mL), dried over MgSO4, filtered and the solvents evaporated under vacuum to give the title compound as a white solid (2.001 g, 94%). 1H NMR (CDCl3, 300 MHz) δ 6.21-4.99 (br s, 1H), 4.49 (br s, 2H), 2.07 (t, J=7.6 Hz, 2H), 1.55-1.40 (m, 2H), 1.34-1.09 (m, 16H), 0.81 (t, J=7.0 Hz, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][N:10]=[CH:11][C:12](=[O:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.[C:15](O)(=[O:17])[CH3:16].C(C=O)=O>CCOC(C)=O>[OH:14][C:12]1[C:11]([C:15](=[O:17])[CH3:16])=[N:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:13]=1
Reactant: COc1cccc(NN=CC(C)=O)c1
Reactant: CC(=O)O
Agent: O=CC=O
Solvent: CCOC(C)=O
Product: COc1cccc(-n2cc(O)c(C(C)=O)n2)c1
Temperature: 25 °C
Yield: 10 %

Procedure:
A mixture of 2-oxopropanal (3-methoxyphenyl)hydrazone (2.88 g, 14.5 mmol), acetic acid (20 mL) and glyoxal (6.3 g, 5.0 mL, 43 mmol) were heated at reflux overnight. The reaction was cooled to room temperature, diluted with EtOAc and washed with saturated aqueous NaCl. The black sludge was removed by decantation and the filtrate was washed with more saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purify by CombiFlash (80 g column, 0-50% heptane/EtOAc gradient) to afford 1-[4-hydroxy-1-(3-methoxyphenyl)-1H-pyrazol-3-yl]ethanone (330 mg, 10%).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:41])[CH2:4][C:5]([NH:7][CH:8]1[C:39](=[O:40])[N:10]2[C:11]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:12]([C:15]3[S:16][C:17]([N:20]([CH3:22])[CH3:21])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6].[N:42]([O-])=[O:43].[Na+]>>[Br:1][CH2:2][C:3](=[O:41])[C:4](=[N:42][OH:43])[C:5]([NH:7][CH:8]1[C:39](=[O:40])[N:10]2[C:11]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=[C:12]([C:15]3[S:16][C:17]([N:20]([CH3:22])[CH3:21])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: O=N[O-]
Reactant: CN(C)c1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)CC(=O)CBr)[C@H]3SC2)s1
Agent: [Na+]
Product: CN(C)c1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NO)C(=O)CBr)[C@H]3SC2)s1
Yield: 88.7 %

Procedure:
By the same procedure as described in Example 1, 0.378 g of benzhydryl 7-(4-bromo-3-oxobutyrylamino)-3-(5-dimethylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate was treated with 0.048 g of sodium nitrite to obtain 0.350 g powdery benzhydryl 7-(4-bromo-3-oxo-2-hydroxyiminobutyrylamino)-3-(5-dimethylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate (syn-isomer).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:4][C:5]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:6][C:7]=1[NH:8][CH3:9].[CH:26](=O)[CH2:27]C.[CH3:30]O>>[CH2:26]([C:9]1[N:8]([CH3:30])[C:7]2[C:2]([N:1]=1)=[C:3]([N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)[N:4]=[C:5]([S:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[N:6]=2)[CH3:27]
Reactant: CO
Reactant: CCC=O
Reactant: CNc1nc(SCc2ccc(OC)cc2)nc(N2CCOCC2)c1N
Product: CCc1nc2c(N3CCOCC3)nc(SCc3ccc(OC)cc3)nc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
5-amino-2-(4-methoxybenzylsulfanyl)-6-methylamino-4-morpholinopyrimidine (693 mg, 1.91 mmol) was dissolved in methanol (20 ml), propionaldehyde (2.76 ml, 38.3 mmol) was added and stirred at room temperature for 3 hours. The solvent was distilled away under reduced pressure, water was added and extracted twice with ethyl acetate. After combining the organic layers and washing with a saturated saline solution, it was dried with MgSO4 and the solvent was distilled away under reduced pressure. Separation and purification were performed by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 610 mg (80% yield) of 8-ethyl-2-(4-methoxybenzylsulfanyl)-9-methyl-6-morpholino-9H-purine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:16][C:17]1[C:22](/[CH:23]=[CH:24]/[N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=[CH:19][C:18]=1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[CH3:16][C:17]1[C:22]([CH:23]([C:3]2[C:4]3[C:9](=[CH:8][C:7]([N:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:24][N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=[CH:19][C:18]=1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: c1cc2ccc(N3CCOCC3)cc2[nH]1
Reactant: Cc1c(/C=C/[N+](=O)[O-])cccc1NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2cc(N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
A solution of 4-(1H-indol-6-yl)morpholine (1.1132 g, 5.50 mmol) and (E)-benzyl 2-methyl-3-(2-nitrovinyl)phenylcarbamate (2.58 g, 8.26 mmol) in THF (50 mL) was concentrated in vacuo. The residue was melted at 137° C. and stirred overnight. After cooling to room temperature, the crude product was purified by flash chromatography using an ISCO 330 g column (solid loading) eluting with 40-80% EtOAc/hexanes to give the desired product (0.9544 g, 1.855 mmol, 33.7% yield) as a light brown solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([CH3:17])[C:10]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:18][OH:19])[CH3:2].[Mn]([O-])(=O)(=O)=[O:21].[K+]>>[CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([CH3:17])[C:10]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[CH:11][C:6]=2[N:5]=[C:4]1[C:18]([OH:21])=[O:19])[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCC(=O)c1cc2nc(CO)n(CC)c2cc1C
Agent: [K+]
Product: CCCC(=O)c1cc2nc(C(=O)O)n(CC)c2cc1C

Procedure:
In a manner analogous to that described in Example 12, 5.2 g of 1-ethyl-5-butyryl-6-methyl-benzimidazole-2-methanol can be oxidised with 4.5 g of potassium permanganate to give 1-ethyl-5-butyryl-6-methyl-benzimidazole-2-carboxylic acid with a melting point>80° (decomposition).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:20]=[C:21]([NH2:24])[S:22][CH:23]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[C:25]1([CH2:31][CH2:32][CH:33]=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl.C([O-])(O)=O.[Na+]>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:20]=[C:21]([NH:24][CH2:33][CH2:32][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:22][CH:23]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CSc1cccc(C(=NOCc2csc(N)n2)c2nnnn2C)c1
Reactant: O=CCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CSc1cccc(C(=NOCc2csc(NCCCc3ccccc3)n2)c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
To a stirred solution of 4-{[({[3-(methylsulfanyl)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}-1,3-thiazol-2-amine (90.0 mg, 0.25 mmol) in dry 1,2-dichloroethane (5 mL), under argon atmosphere, were added 3-phenylpropionaldehyde (63.5 mg, 0.47 mmol), acetic acid (89.7 mg, 1.49 mmol) and sodium triacetoxyborohydride (156 mg, 0.70 mmol) at room temperature. After stirring at room temperature for 18 h, 3-phenylpropionaldehyde (63.5 mg, 0.47 mmol), acetic acid (89.7 mg, 1.49 mmol) and sodium triacetoxyborohydride (156 mg, 0.70 mmol) were added again and the reaction mixture was further stirred at room temperature for 20 h. The reaction mixture was diluted with dichloromethane (10 mL) and sat. aq. NaHCO3 (10 mL) was added. After phase separation, the aqueous layer was washed with ethyl acetate (3×10 mL), the combined organic layers were washed with water (10 mL), dried over MgSO4 and concentrated in vacuo. Purification on silica gel afforded 4-{[({[3-(methylsulfanyl)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}-N-(3-phenylpropyl)-1,3-thiazol-2-amine as a pale yellow oil [69 mg, yield 58%; HPLC/MS m/z=481 (M+H); logP(HCOOH)=3.71].
Reaction SMILES: [CH:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23]([O:25][CH3:26])=[O:24]>>[CH3:26][O:25][C:23]([CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[NH:16][C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:12]=1)=[O:15])=[O:24]
Reactant: O=C(O)c1cccc(C2CCCCC2)n1
Reactant: COC(=O)C1CCCCC1N
Product: COC(=O)C1CCCCC1NC(=O)c1cccc(C2CCCCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclohexyl-pyridine-2-carboxylic acid (Example 7 b) and methyl 2-aminocyclohexane-1-carboxylate (CAN 40015-88-1) as starting materials, MS (EI): m/e=345.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([Cl:21])[CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[Cl:21][C:12]1[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:22]=[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][C:17]([F:20])([F:19])[F:18]
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(Cl)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(Cl)c1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (R)-5-bromo-N-(3-chloro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 204.1) and pyrimidin-5-ylboronic acid to afford a white foam. HPLC (Condition 4) tR=5.17 min, UPLC-MS (Condition 3) tR=1.03 min, m/z=480.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.74 (m, J=3.90 Hz, 1H) 1.79-1.93 (m, 1H) 2.88 (d, J=11.34 Hz, 1H) 3.21 (m, J=11.10, 4.50 Hz, 2H) 3.37 (m, J=7.00 Hz, 1H) 4.11-4.25 (m, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.55 (d, J=8.99 Hz, 1H) 7.72-7.86 (m, 1H) 8.10 (dd, J=15.84, 2.54 Hz, 2H) 8.74-8.81 (m, 1H) 8.88 (s, 2H) 9.19 (s, 1H) 10.27 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][CH3:10])[C:3]=1[CH2:11][C:12](Br)(Cl)Cl.C[O-:17].[Na+].S(=O)(=O)(O)O.[C:24]([O-])(O)=[O:25].[Na+]>CO.O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][CH3:10])[C:3]=1[CH2:11][C:12]([O:25][CH3:24])=[O:17]
Reactant: C[O-]
Reactant: CCc1cc(Cl)cc(Br)c1CC(Cl)(Cl)Br
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCc1cc(Cl)cc(Br)c1CC(=O)OC
Temperature: 25 °C

Procedure:
To a solution of 15.8 g [0.04 mol] of 1-bromo-2-(2′-bromo-2′,2′-dichloroethyl)-5-chloro-3-ethylbenzene in 35 ml of methanol is added dropwise, at 10-20° C., 43 g of a 30% solution of NaOMe in MeOH [0.24 mol]. The mixture is subsequently heated to reflux for 5 hours, then cooled to room temperature, 12.3 g of conc. sulphuric acid are added and the mixture is heated again to reflux for 2 hours. The reaction mixture is cooled to room temperature and then metered in portions into a suspension of 12.7 g of NaHCO3 in 80 ml of water, stirred with 50 ml of methylene chloride and filtered through silica gel, and the filtercake is washed three times with 20 ml each time of methylene chloride. The combined organic phases are extracted by shaking with 20 ml of water and then 20 ml of saturated aqueous NaCl solution, dried over sodium sulphate and concentrated under reduced pressure. This gives 11.55 g of methyl 2-bromo-4-chloro-6-ethylphenylacetate (99% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.CC[OH:15]>>[NH2:10][C:4]1[C:5]([C:8]([NH2:9])=[O:15])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: N#Cc1ncc(Cl)cc1[N+](=O)[O-]
Reactant: CCO
Product: NC(=O)c1ncc(Cl)cc1N
Reaction time: 2.5 h

Procedure:
Raney Nickel (10 g of Aldrich 50% slurry in water) was washed with water (100 mL), 5% AcOH (100 mL), water (100 mL), and 95% EtOH (3×100 mL). The resulting slurry was added to a solution of 5-chloro-3-nitropicolinonitrile (104) (5.0 g, 27 mmol) in 95% EtOH (100 mL). The mixture was hydrogenated at 45 psi for 2.5 h. The mixture was then filtered over a bed of Celite and washed with 95% EtOH (2×100 mL). The red/brown filtrate was rota-evaporated to dryness, leaving the title compound as a light brown solid, 3.8 g (82%), mp 152°-6° C. (Lit., 165°-6° C., McCaustland and Cheng, J. Heterocycl. Chem. 7:467 (1970)); 1H NMR (CDCl3): δ5.42 (bs, 1H), 6.05 (bs, 2H), 7.00 (d, J=1.2 Hz, 1H), 7.71 (bs, 1H), 7.79 (d, J=1.2 Hz, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[NH:12][C:11]2[C:6]1=[N:7][C:8]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si](C(C)C)(C(C)C)C(C)C)[CH:20]=1)=[N:9][C:10]=2[C:15]([O:17]C)=O)[CH:2]([CH3:4])[CH3:3].[NH2:36]C1C(C(OC)=O)=NC(C2C=CC=C(O[Si](C(C)C)(C(C)C)C(C)C)C=2)=NC=1NC1C2C(=CC=CC=2)CC1>ClCCl>[OH:25][C:21]1[CH:20]=[C:19]([C:8]2[N:7]=[C:6]3[C:11]([NH:12][C:13](=[O:14])[N:5]3[CH2:1][CH:2]([CH3:3])[CH3:4])=[C:10]([C:15]([NH2:36])=[O:17])[N:9]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1nc(-c2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2)nc2c1[nH]c(=O)n2CC(C)C
Reactant: COC(=O)c1nc(-c2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2)nc(NC2CCc3ccccc32)c1N
Solvent: ClCCl
Product: CC(C)Cn1c(=O)[nH]c2c(C(N)=O)nc(-c3cccc(O)c3)nc21
Yield: 85 %

Procedure:
Methyl 9-isobutyl-8-oxo-2-(3-(triisopropylsilyloxy)phenyl)-8,9-dihydro-7H-purine-6-carboxylate. Methyl 5-amino-6-(2,3-dihydro-1H-inden-1-ylamino)-2-(3-(triisopropylsilyloxy)phenyl)pyrimidine-4-carboxylate (0.300 g, 0.635 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.411 g, 2.54 mmol) in dichloromethane (25 mL) were reacted according to General Procedure F. The solution was condensed under reduced pressure and partitioned between water and ethyl acetate (3×). Organic fractions were combined and dried over magnesium sulfate, filtered and solvent removed under reduced pressure. The crude solid was diluted with methanol (15 mL) and sonicated. The resulting precipitate was filtered to afford the title compound (0.185 g, 85%). MS (ESI) m/z 268.2 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC=O
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.4 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (14 g, 43 mmol) and acetaldehyde (3.75 g, 85.4 mmol) in dichloroethane (150 mL), was added acetic acid (15.36 g, 256 mmol). After stirring at room temperature for 20 minutes, sodium triacetoxyborohydride (27.0 g, 128 mmol) was added at 0° C. The mixture was stirred at room temperature for 2 h. and quenched with aqueous sodium bicarbonate. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to give crude material which was purified by column chromatography over silica gel to afford methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (14 g, 93%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[CH3:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][NH:27][CH3:28].[CH2:30]=O>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:22][N:23]([CH2:24][CH2:25][CH2:26][N:27]([CH3:30])[CH3:28])[CH3:29])=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2cc(O)ccc21
Reactant: CNCCCN(C)C
Reactant: C=O
Solvent: CCO
Product: CN(C)CCCN(C)Cc1c(O)ccc2c1O/C(=C\c1c[nH]c3ccccc13)C2=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A solution of (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (0.030 g, 0.11 mmol) obtained in Example A1, Step 1 in ethanol (2.0 mL) was added with N,N,N′-trimethylpropane-1,3-diamine (0.015 g, 0.13 mmol), and 37% aqueous formaldehyde (0.011 g, 0.13 mmol), and the mixture was stirred overnight at 80° C. in a sealed tube. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain (Z)-2-[(1H-indol-3-yl)methylene]-7-({[3-(dimethylamino)propyl](methyl)amino}methyl)-6-hydroxybenzofuran-3(2H)-one (0.024 g, 54%).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH:15]([NH2:17])=O.Br[CH:19]1[C:24](=O)[CH2:23][CH2:22][CH2:21][CH:20]1[C:26]([O:28][CH3:29])=[O:27]>O1CCOCC1>[S:2]1[C:19]2[CH:20]([C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:22][CH2:23][C:24]=2[N:17]=[CH:15]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)C1CCCC(=O)C1Br
Reactant: NC=O
Solvent: C1COCCO1
Product: COC(=O)C1CCCc2ncsc21
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
At 0° C., finely crushed P4S10 (9.35 g, 21.0 mmol) was added to a mixture of formamide (4.73 g, 105.0 mmol) in dioxane (28.5 mL). Subsequently, the mixture was stirred in a sealed vial at 100° C. for 1.5 h, cooled to RT and filtrated. The filtrate was added to a mixture of methyl 2-bromo-3-oxocyclohexanecarboxylate (2.06 g, 8.76 mmol) in dioxane (16.5 mL) and stirred in a sealed vial at 80° C. overnight. The mixture was quenched by the addition of aq. sat. NaHCO3 and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. Purification by means of CC (10-40% EtOAc/Hept) provided a yellow oil.