Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]([CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[N:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])#[N:2].[BH4-].[Na+].CC(C)=O>C(O)C>[C:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:11][CH:10]=2)[C:6]([CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[N:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH:34]([OH:39])[C:35]([F:38])([F:36])[F:37])#[N:2]
Reactant: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCCc1nc(-n2cccc2C(O)C(F)(F)F)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 1 h

Procedure:
A solution of 5-cyano-4-[2-(1-oxo-2,2,2-trifluoroethyl)-1H-pyrrol-1-yl]-2 propyl-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole (Example 27, 300 mg) in ethanol (5 mL) was chilled to 10° C. and treated with NaBH4 (30 mg). There was a period of rapid gas evolution then the reaction was stirred for 1 hour. Acetone (0.1 mL) was added and the reaction was stirred 10 minutes longer before partitioning between ethyl acetate and 10% citric acid (aq). The organic layer was washed with saturated aqueous NaCl, dried over MgSO4 and evaporated. Flash chromatography on silica gel, eluting with CHCl3CH3OH--CH3CN (90:5:5) gives the title compound as a foam upon evaporation of solvents. The foam was triturated with hexane diisopropyl ether (3:1) to give a colorless powder. MS (FAB, thioglycerol) 533 (m+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([CH3:15])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C1COCC1>[Cl:23][CH2:24][C:25]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([CH3:15])[N:9]=2)=[CH:4][CH:3]=1)=[O:26]
Reactant: Cc1cc(O)nc(-c2ccc(N)cn2)n1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(O)nc(-c2ccc(NC(=O)CCl)cn2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound of example 13 (0.10 g, 0.49 mmol) in THF (5 mL) was added triethylamine (0.075 g, 0.742 mmol) and chloroacetylchloride (0.0559 g, 0.495 mmol), and the reaction mixture was stirred at room temperature for 2 hours. THF was removed under reduced pressure, and the reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by crystallization from ethyl acetate and petroleum ether to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]2[CH2:17][CH2:16][CH:15]([N:18]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].O.NN>C(Cl)(Cl)Cl.C(O)C>[CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:12]2[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OC2CCC(N3C(=O)c4ccccc4C3=O)CC2)cc1
Agent: NN
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1ccc(OC2CCC(N)CC2)cc1
Temperature: 7.5 °C
Reaction time: 48 h
Yield: 98.5 %

Procedure:
To a solution of 4-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-cyclohexyloxy]-benzoic acid ethyl ester (6.3 g, 16.0 mmol) in CHCl3 (50 mL) and ethanol (60 mL) was added hydrazine hydrate (16.0 g, 320.2 mmol). Stirring was continued at ambient temperature for 2 days. The reaction mixture was then cooled to 5-10° C. and the white precipitate was filtered off. The filtrate was washed with water, dried and the solvent evaporated under vacuum to afford 4.15 g (98%) of 4-(4-amino-cyclohexyloxy)-benzoic acid ethyl ester.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].Cl[CH2:15][CH2:16][CH2:17][CH3:18].[C-:19]#[N:20].[Na+].[I-].[Na+]>CN(C)C=O>[N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:18][CH2:17][CH2:16][CH2:15][C:19]#[N:20])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2]
Reactant: CCCCCl
Reactant: [C-]#N
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2CCCCC#N)n(C)c1=O
Yield: 73 %

Procedure:
2.7 g. of theophylline-chloro-butane according to Example b., 0.51 g. of sodium cyanide, 0.01 g. of sodium iodide and 10 cm3 of dimethylformamide are heated at 95° C. for 5 hours. Thus 1.9 g. (73% yield) of δ-(theophylline-7- yl)-valeronitrile are obtained, m.p.: 118°-120° C. (ethylacetate).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11](=[O:29])[C@@H:12]([NH:14][C:15](=[O:28])[C@@H:16]([NH:20]C(OC(C)(C)C)=O)[CH:17]([CH3:19])[CH3:18])[CH3:13])[NH:6]1)=[O:4].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11](=[O:29])[C@@H:12]([NH:14][C:15](=[O:28])[C@@H:16]([NH2:20])[CH:17]([CH3:18])[CH3:19])[CH3:13])[NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CCCN(C(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)N1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN(C(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid methyl ester (150 mg, 0.36 mmol) in dichloromethane (5 mL) was stirred at 0° C. under nitrogen. Trimethylsilyl trifluoromethanesulfonate (160 mg, 0.13 mL, 0.72 mmol) was added and the reaction mixture was stirred at 0° C. for 1 hour. N,N-Diisopropylethylamine (186 mg, 0.25 mL, 1.44 mmol) was added and the solvent was evaporated to afford (S)-1-[(S)-2-((S)-2-amino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid methyl ester (0.36 mmol) as a white solid which was used without further purification. A solution of 75f (134 mg, 0.33 mmol) in acetonitrile was stirred at 0° C. under nitrogen. A solution of (S)-1-[(S)-2-((S)-2-amino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid methyl ester (0.36 mmol) and N,N-diisopropylethylamine (129 mg, 0.17 mL, 1.0 mmol) in acetonitrile (5 mL) was added followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (175 mg, 0.46 mmol) and the reaction mixture was stirred at 0° C. for 10 min and then at RT for 1 hour. The solvent was evaporated and the residue was apportioned between ethyl acetate and water. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using iso-hexane/ethyl acetate 1:5 to ethyl acetate to afford the title compound (165 mg, 72%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.B(O)(O)[C:17]1[CH:22]=[N:21][CH:20]=[N:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[N:19]1[CH:18]=[C:17]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:22]=[N:21][CH:20]=1
Reactant: OB(O)c1cncnc1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cn1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(Oc2ccnc(-c3cncnc3)c2)cn1
Temperature: 95 °C
Yield: 21.7 %

Procedure:
A solution of Example A9 (0.25 g, 1.128 mmol) and pyrimidinyl-5-boronic acid (0.196 g, 1.579 mmol) in dioxane (8 mL) was treated with a solution of K2CO3 (0.156 g, 1.128 mmol) in water (2 mL), Pd(PPh3)4 (0.130 g, 0.113 mmol) and heated at 95° C. for 20 h. The mixture was cooled to RT, treated with water and extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 5-((2-(pyrimidin-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (65 mg, 22%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 2H), 9.24 (s, 1H), 8.55 (d, J=5.7 Hz, 1H), 7.84 (d, J=3.0 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.32 (dd, J=8.9, 3.0 Hz, 1H), 6.83 (dd, J=5.7, 2.4 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.04 (s, 2H); MS (ESI) m/z: 266.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[S:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1>C(=S)=S>[Cl:1][C:2]1[C:3]([C:4]([C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: c1ccsc1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(c1cccs1)c1cccnc1Cl
Temperature: 25 °C

Procedure:
10 g of 2-chloronicotinic acid chloride was added to a mixture of 7.2 g of aluminum chloride and 100 ml of carbon disulfide under ice-cooling, followed by adding 8.8 ml of thiophene was slowly added dropwise thereinto. After stirring at room temperature for two nights, the reaction solution was slowly poured into ice water. The mixture was extracted with ethyl acetate, and the organic phase was successively washed with aqueous saturated sodium bicarbonate and brine. After removing the solvent, the residue was subjected to silica gel column chromatography and eluted with hexane/ethyl acetate (3:1) and then with hexane/ethyl acetate (2:1), to give 1.64 g of the target compound.
Reaction SMILES: [CH3:1][C@@:2]12[O:9][C@@H:6]([CH2:7][CH2:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([Pb+3])=[C:31]([CH2:36][CH3:37])[CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([CH:4]2[C:5](=[O:10])[C@H:6]3[O:9][C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:11])=[C:31]([CH2:36][CH3:37])[CH:30]=1
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Reactant: CCc1cc(Br)ccc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1cc(Br)ccc1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 45.7 %

Procedure:
(1R*,5S*)-1-Methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (6 g, 38.96 mmol) and 4-dimethylaminopyridine (23.76 g, 194.75 mmol) are added to a mixture of chloroform (120 ml) and toluene (30 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2-ethylphenyllead triacetate (24.3 g, 42.85 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases separated. The aqueous phase is extracted with dichloromethane (2×50 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1R*,5S*)-3-(4-bromo-2-ethylphenyl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione as a white solid (6 g).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[C:9]([CH3:15])[CH:10]=[CH:11][C:12]=2[CH3:14])[N:7]=[C:6](O)[CH:5]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:19]>C1(C)C=CC=CC=1>[Cl:19][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]2[C:8](=[C:9]([CH3:15])[CH:10]=[CH:11][C:12]=2[CH3:14])[N:7]=1
Reactant: Cc1ccc(C)c2c(C(C)C)cc(O)nc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c2c(C(C)C)cc(Cl)nc12
Yield: 71 %

Procedure:
A solution of 4-isopropyl-5,8-dimethylquinolin-2-ol (1.30 g, 6.05 mmol), 700 L (1.2 eq) of POCl3 in toluene were reacted as outlined in Scheme 1 above to yield 1.00 g of 2-chloro-4-isopropyl-5,8-dimethylquinoline (71%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.34 (d, J=6.74 Hz, 6 H) 2.71 (s, 3 H) 2.87 (s, 3 H) 4.12 (quin, J=6.74 Hz, 1 H) 7.21 (d, J=7.33 Hz, 1 H) 7.32 (s, 1 H) 7.40 (d, J=7.33 Hz, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:25](C)=O.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(O)(=O)C>[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:25][NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:13]1
Reactant: Cn1c(C=O)cc2ccccc21
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cn1cc(CNc2ccccc2[N+](=O)[O-])c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
2-nitroaniline (829 mg, 6 mmol) and 1-methylindole carboxaldehyde (1242 mg, 7.8 mmol) were dissolved in 20 ml of tetrahydrofuran, to which acetic acid (200 μl) and NaBH(OAc)3 (5087 mg, 24 mmol) were sequentially added and stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate, dried with anhydrous sodium sulfate, and the solvent was evaporated. After purification by silica gel column chromatography (hexane:ethyl acetate=95:5), ((1-methylindole-3-yl)methyl)(2-nitrophenyl)amine was obtained (264 mg, yield 18%).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16]SC2SC3C=CC=C(C)C=3N=2)[N:14]([CH:28]([C:47]([CH3:49])=[CH2:48])[C:29]([O:31][CH2:32][C:33]2[C:38]([Cl:39])=[C:37]([O:40][CH3:41])[C:36]([O:42][CH3:43])=[C:35]([O:44][CH3:45])[C:34]=2[Cl:46])=[O:30])[C:13]1=[O:50])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:51]1([S:57](C#N)(=[O:59])=[O:58])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C1(S([O-])=O)C=CC=CC=1.[Na+]>CC(C)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:57]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)(=[O:59])=[O:58])[N:14]([CH:28]([C:47]([CH3:49])=[CH2:48])[C:29]([O:31][CH2:32][C:33]2[C:34]([Cl:46])=[C:35]([O:44][CH3:45])[C:36]([O:42][CH3:43])=[C:37]([O:40][CH3:41])[C:38]=2[Cl:39])=[O:30])[C:13]1=[O:50])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: C=C(C)C(C(=O)OCc1c(Cl)c(OC)c(OC)c(OC)c1Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2c(C)cccc2s1
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(C)C(C(=O)OCc1c(Cl)c(OC)c(OC)c(OC)c1Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Yield: 85 %

Procedure:
A 268 mg quantity of 3,4,5-trimethoxy-2,6-dichlorobenzyl 2-[3-phenoxyacetamido-4-(4-methylbenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 69 mg of benzenesulfonyl cyanide were dissolved in 3 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 5 was followed, producing 3,4,5-trimethoxy-2,6 dichlorobenzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 85%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. The NMR spectrum data are shown below in Table 2.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.Cl.[C:24](Cl)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O.ClCCl>[C:24]([NH:6][C@@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[C:4]([O:3][CH3:2])=[O:15])(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC(=O)Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Reaction time: 3.5 h
Yield: 92.4 %

Procedure:
200 ml of dichloro methane (DCM) was added to (L)-tyrosine methyl ester HCl salt (23.16 g, 0.1 mol), and 28 ml of triethyl amine (TEA, 0.2 mol) was added thereto, thereby dissolving HCl salt. The reactor was temperature-lowered to 0° C. by using an ice bath, and hexanoyl chloride (13.8 ml, 0.1 mol) was slowly added, following by stirring for 3-4 hours. 200 ml of water was added to the reacted material, followed by extraction with 400 ml of ethyl acetate. Drying over sodium sulfate followed by filtering was carried out. The solvent was removed from the filtrate by rotary evaporation, followed by solidification with hexane and ethyl acetate, thereby obtaining a white solid (27.1 g, 92.5% yield) [hereinafter, referred to as Compound 1a].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20](C(OCC)=O)[CH:19]=[C:18]([C:27]3[CH:32]=[CH:31][C:30]([C:33](F)([F:35])F)=[CH:29][CH:28]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C[Mg]Cl.[C:40](=O)([O-])[O-].[Na+].[Na+].[O:46]1[CH2:50][CH2:49]CC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:50]([OH:46])([CH3:49])[CH3:40])[CH:19]=[C:18]([C:27]3[CH:28]=[CH:29][C:30]([CH2:33][F:35])=[CH:31][CH:32]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: C[Mg]Cl
Agent: [Na+]
Product: COc1cc(Nc2nc(-c3ccc(CF)cc3)cc(C(C)(C)O)n2)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
To a solution of ethyl 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-carboxylate (597 mg, 1.2 mmol) in tetrahydro-furane (25 mL) was added at 0° C. over 2 min a 3 M solution of methylmagnesiumchloride in tetrahydrofurane (1.68 mL, 5.04 mmol). The reaction mixture was stirred at 0° C. for 15 min followed by 1.5 h at 20° C. The mixture was poured on saturated sodium carbonate solution (20 mL) and the product was extracted with ethyl acetate (80 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using dichloromethane/0-10% methanol as eluent. Following a more liopophilic by-product (54 mg, example 175) the title compound was eluted and crystallized from dichloromethane/diethyl ether to give a white solid (314 mg, 54%). MS ISP (m/e): 484.4 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.21 (d, 2H), 7.82 (d, 1H), 7.77 (d, 2H), 7.66 (s, 1H), 7.36 (s, 2H), 7.22 (d, 1H), 7.10 (dd, 1H), 6.90 (s, 1H), 3.90 (s, 3H), 3.84 (br s, 1H), 2.31 (s, 3H), 1.56 (s, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([CH:18]=[CH2:19])[CH:15]=[C:14]([C:20]#[N:21])[CH:13]=2)[O:9][N:8]=1.C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.B1([O-])O[O:43]1.O.O.O.O.[Na+]>ClCCl.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([CH2:18][CH2:19][OH:43])[CH:15]=[C:14]([C:20]#[N:21])[CH:13]=2)[O:9][N:8]=1
Reactant: C=Cc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#Cc1cc(CCO)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 3.9 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-vinylphenyl)-1,2,4-oxadiazole (83 mg, 0.30 mmol) in dichloromethane (2 mL) was treated with 9-BBN dimer (40 mg, 0.16 mmol) and the reaction mixture stirred at room temperature for 4 hours. Sodium perborate tetrahydrate (157 mg, 1.02 mmol) and water (1 mL) were added and the resulting biphasic mixture was stirred vigorously for 18 hours. The mixture was diluted with dichloromethane and water and the organic layer dried by filtration through an EX-TUBE. Silica gel chromatography using a gradient of 20% to 75% ethyl acetate in hexane, followed by trituration in 10% ethyl acetate in hexane afforded 3.4 mg (3.7%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-hydroxyethyl)phenyl)-1,2,4-oxadiazole: 1H-NMR (CDCl3), δ (ppm):08.85 (d, 1H), 8.43 (s, 2H), 8.22 (d, 1H), 7.90 (t, 1H), 7.80 (s, 1H), 7.48 (m, 1H), 3.99 (m, 2H), 3.02 (t, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=1[CH2:25][CH2:26][CH3:27]>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:12][CH2:13]3)[C:9]=2[CH:10]=1
Reactant: O=C(O)c1cc(Br)cc2c1cnn2C1CC1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C1CC1
Reaction time: 12 h

Procedure:
The title compound was prepared in the same manner as described for example 3 (step c) from 6-bromo-1-cyclopropyl-1H-indazole-4-carboxylic acid (0.22 g, 0.783 mmol) and 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (0.236 g, 1.089 mmol), wherein the reaction stir time was 12 h. The title compound was collected as a white solid (0.36 g, 91%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (t, J=7.33 Hz, 3H), 1.06-1.16 (m, 4H), 1.50 (sxt, J=7.53 Hz, 2H), 2.13 (s, 3H), 3.76-3.86 (m, 1H), 4.36 (d, J=5.05 Hz, 2H), 5.90 (s, 1H), 7.74 (d, J=1.52 Hz, 1H), 8.09 (s, 1H), 8.31 (s, 1H), 8.64 (t, J=4.80 Hz, 1H), 11.54 (br. s., 1H); LC-MS (ES) m/z=443.0 [M+H].
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1)=O.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:13][C:5]1[CH:4]=[C:3]([CH2:1][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(C=O)cc1C
Reactant: C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CN2CCCCC2)cc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.5 %

Procedure:
To a solution of methyl 4-formyl-2-methylbenzoate (300 mg, 1.7 mmol) and piperidine (92 mg, 1.1 mmol) in methanol (50 mL) was added acetic acid (1 drop) followed by sodium cyanoborohydride (221 mg, 3.5 mmol). The mixture was stirred at room temperature for 24 hours. The mixture was filtered, acidified with concentrated hydrochloride acid (1 mL) and concentrated in vacuo. To the residue, water (50 mL) was added. The mixture was extracted with dichloromethane (50 mL). The combined organic phase was separated, dried by sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=4:1, 1% NH3) to give methyl 2-methyl-4-(piperidin-1-ylmethyl)benzoate as a yellow oil (200 mg, 60%). LRMS (M+H+) m/z: calcd 247.16. found 247. 1H NMR (300 MHz, CDCl3): δ 7.73 (d, J=8.7 Hz, 1H), 7.52-7.50 (m, 2H), 3.91 (s, 3H), 3.62 (s, 2H), 2.52 (s, 3H), 2.32-2.24 (m, 4H), 1.47-1.44 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[N:11]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: COC(=O)c1cccc(Br)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Br)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
To a solution of 0.413 g (1.03 mmol) of the product of Example 198 in 10 mL of DMF was added 0.062 g (1.55 mmol) of 60% sodium hydride. Stirring was continued for 15 min at 25° C. and 0.125 mL (1.442 mmol) of benzyl bromide was then added and the mixture was stird for 18 h at 55° C. The reaction was cooled to room temperature and the reaction mixture was poured into 200 mL water and 50 mL 1N HCl. The aqueous layer was then extracted with dichlromethane (100 mL) and ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica eluting with 10%-20% ethyl acetate/hexane to provide 0.390 g (77%) of the desired product. Electrospray Mass Spec 490.0 (M+H)