Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH3:20][NH:21][CH3:22].C1COCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:20][N:21]([CH3:22])[CH2:1][C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CSc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C[C@H](CSc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
A solution of Example 134A (1.25 g, 4.44 mmol), 2M dimethylamine in THF (2.7 mL, 5.4 mmol), and NaBH(OAc)3 (1.32 g, 6.22 mmol) in dichloromethane at room temperature was stirred for 18 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product. MS (ESI(+)) m/e 311 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:32])([CH3:31])[CH2:3][C@@:4]1([CH:28]([CH3:30])[CH3:29])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:34]1[CH:35]=[N:36][C:37]([C:40]([OH:42])=[O:41])=[N:38][CH:39]=1>>[OH:1][C:2]([CH3:31])([CH3:32])[CH2:3][C@@:4]1([CH:28]([CH3:30])[CH3:29])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:34]3[CH:35]=[N:36][C:37]([C:40]([OH:42])=[O:41])=[N:38][CH:39]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: CC(C)[C@@]1(CC(C)(C)O)CCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Product: CC(C)[C@@]1(CC(C)(C)O)CCN([C@@H](C)c2ccc(-c3cnc(C(=O)O)nc3)cc2)C(=O)O1

Procedure:
5-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)pyrimidine-2-carboxylic acid was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromopyrimidine-2-carboxylic acid following a procedure analogous to that described in Example 1 Step 2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC([N+](C(OCC)=O)=[N-])=O)C.[OH:32][C:33]1[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:35][N:34]=1.[Br:44][CH2:45][CH2:46]O>C1(C)C=CC=CC=1>[Br:44][CH2:45][CH2:46][O:32][C:33]1[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:35][N:34]=1
Reactant: OCCBr
Reactant: Oc1cc(-c2ccccc2)on1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: BrCCOc1cc(-c2ccccc2)on1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
Triphenylphosphine (15.7 g) was dissolved in toluene (200 ml), and the solution was cooled to 5° C. Diethyldiazodicarboxylate (10.4 g) was added to the solution, and the resulting mixture was stirred at the same temperature for 10 minutes. Then, 3-hydroxy-5-phenylisoxazole (8.0 g) and 2-bromoethanol (7.5 g) were added in this order to the reaction mixture, followed by stirring of the resulting mixture at room temperature for 10 minutes and further at room temperature for 2 hours. Insolubles were filtered off from the mixture, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to obtain the title compound (12.1 g, 90%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[O:11][C:10]2=[O:20])[CH:5]=[CH:4][N:3]=1.[N:21]([CH3:24])=[C:22]=[O:23]>N1C=CC=CC=1>[O:20]=[C:10]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:22]([NH:21][CH3:24])=[O:23])[CH:7]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[O:11]1
Reactant: CN=C=O
Reactant: Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Solvent: c1ccncc1
Product: CNC(=O)Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1

Procedure:
To a stirred solution of 1-(2-amino-pyridin-4-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (7.0 g, see preparation 7b) in pyridine (70 ml) was added isocyanatomethane (5 eq.) over 45 minutes. More isocyanatomethane (in total 20 eq.) was added over time until all starting material had been consumed. The solvent was evaporated under reduced pressure. The remaining solid material washed with EtOAc (50 ml) and gave 1-[4-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-pyridin-2-yl]-3-methyl-urea after drying in vacuo. Step 2: This anhydride intermediate was converted into the title compound by reaction with O-(4-cyanobenzyl)hydroxylamine hydrochloride (see preparation 10), using general procedure 1A. 13C-NMR (DMSO-d6) δ 167.4, 155.3, 153.7, 151.2, 148.5, 146.6, 141.8, 132.6, 132.2, 129.2, 128.0, 118.7, 115.1, 114.7, 112.9, 111.5, 110.8, 109.1, 76.0, 45.2, 25.8.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1)[CH2:3]Br.[OH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>C(O)C.C1C=CC=CC=1>[OH:1][CH:2]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1)[CH2:3][N:20]1[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]1
Reactant: OC1CCNCC1
Reactant: OC(CBr)c1cc(-c2ccccc2)on1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: OC1CCN(CC(O)c2cc(-c3ccccc3)on2)CC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 62.5 %

Procedure:
A mixture of 3-(1-hydroxy-2-bromoethyl)-5-phenylisoxazole (268 mg) and 4-hydroxypiperidine (121 mg) is dissolved in a mixture (4 ml) of 99% ethanol and benzene (1:1). To the solution is added sodium hydrogen carbonate (168 mg) and stirred at 70°C for 5 hours. After removal of the solvent, the residue is subjected to a column chromatography (silica gel,) eluted with a mixture of methylene chloride and methanol, and the crude crystals collected are recrystallized from ethyl acetate to give 3-[1-hydroxy-2-(4-hydroxypiperidino)ethyl]-5-phenylisoxazole (180 mg) as colorless prisms melting at 117-119°C.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7](=[O:19])[NH:8][C:9]3[CH:10]=[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]4=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].[C:33]([O:37][C:38](=[O:44])[NH:39][CH2:40][CH2:41][CH2:42]Br)([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C>[C:33]([O:37][C:38]([NH:39][CH2:40][CH2:41][CH2:42][N:8]1[C:9]2[CH:10]=[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]3=[CH:13][C:14]=2[C:5]2=[N:4][N:3]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:2](=[O:1])[N:6]2[C:7]1=[O:19])=[O:44])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)n1nc2c3cc4ccccc4cc3[nH]c(=O)n2c1=O
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCn1c(=O)n2c(=O)n(C(=O)OC(C)(C)C)nc2c2cc3ccccc3cc21
Temperature: 23 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl 3,5-dioxo-5,6-dihydrobenzo[g][1,2,4]triazolo[4,3-c]quinazoline-2(3H)-carboxylate (8-6, 28 mg, 0.079 mmol, 1 equiv), cesium carbonate (100 mg, 0.31 mmol, 3.8 equiv), and N-(3-bromopropyl)carbamic acid tert-butyl ester (50 mg, 0.21 mmol, 2.6 equiv) in DMF (3 mL) was stirred at 23° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated and purified by reverse phase liquid chromatography (H2O/CH3CN gradient w/0.1% TFA present) to yield tert-butyl 6-{3-[(tert-butoxycarbonyl)amino]propyl}-3,5-dioxo-5,6-dihydrobenzo[g][1,2,4]triazolo[4,3-c]quinazoline-2(3H)-carboxylate (8-7).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][NH:8]C(OC(C)(C)C)=O)(=[O:4])=[O:3].C(O)C.[ClH:19]>CO>[ClH:19].[NH2:8][CH2:7][CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NCCNS(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CS(=O)(=O)NCCN
Yield: 79.3 %

Procedure:
In a 500 ml reaction flask, tert-butyl 2-methylsulfonamidoethylaminoformate (25 g) and 350 ml of a mixture of ethanol and methanol were added. The mixture was stirred by an electromagnetic stirrer, fed with dry hydrogen chloride gas for 3 h, stirred at room temperature overnight, concentrated under a reduced pressure to a small volume, subjected to suction filtration to obtain 14.6 g of brown-gray powdery solid, yield 79.3%.
Reaction SMILES: CC[O-].[Na+].[CH2:5]([O:7][C:8]([CH2:10][C:11]([CH3:17])([CH3:16])[CH:12](Br)[C:13]#[N:14])=[O:9])[CH3:6].O.Cl>C(O)C>[CH2:5]([O:7][C:8]([CH:10]1[C:11]([CH3:17])([CH3:16])[CH:12]1[C:13]#[N:14])=[O:9])[CH3:6]
Reactant: CCOC(=O)CC(C)(C)C(Br)C#N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1C(C#N)C1(C)C
Reaction time: 3 h
Yield: 69 %

Procedure:
8.15 g (0.12 mol) of sodium ethylate in 30 ml of ethanol were added dropwise to a solution of 24.8 g (0.1 mol) of 3-bromo-3-cyano-2,2-dimethyl-propane-1-carboxylic acid ethyl ester in 50 ml of ethanol. The mixture was subsequently stirred at 50°-60° C. for 3 hours. 200 ml of water were then added and the reaction mixture was neutralized with HCl and extracted twice with 50 ml of methylene chloride each time. The combined methylene chloride extracts were washed twice with 50 ml of H2O each time, dried over Na2SO4 and then concentrated. The residue was fractionated. 11.5 (69% theory) of 2-cyano-3,3-dimethyl-cyclopropane-1-carboxylic acid ethyl ester were obtained in the form of a colorless oil of boiling point 68°-72° C./2 mm Hg.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[C:22]([O:26][C:27]([NH:29][C:30]12[CH2:37][CH2:36][C:33]([C:38](O)=[O:39])([CH2:34][CH2:35]1)[CH2:32][CH2:31]2)=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)Cl>O>[S:12]([N:9]1[C:6]2=[N:7][CH:8]=[C:3]([NH:1][NH:2][C:38]([C:33]34[CH2:34][CH2:35][C:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])([CH2:31][CH2:32]3)[CH2:37][CH2:36]4)=[O:39])[N:4]=[C:5]2[CH:11]=[CH:10]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: CC(C)(C)OC(=O)NC12CCC(C(=O)O)(CC1)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)C45CCC(NC(=O)OC(C)(C)C)(CC4)CC5)cnc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
A round bottom flask was charged with 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (3.75 g, 11.1 mmol, Preparation #9), 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (3.0 g, 11 mmol, Prime Organics), HATU (4.23 g, 11.1 mmol), TEA (6.2 mL, 44 mmol), and DCM (65 mL). The reaction mixture was stirred at ambient temperature for about 16 h. The reaction mixture was diluted with water (30 mL) and the layers were separated. The reaction mixture was filtered through Celite® and washed with DCM (60 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in DCM to afford tert-butyl 4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)bicyclo[2.2.2]octan-1-ylcarbamate as a brown amorphous solid (5.38 g, 87%): LC/MS (Table 2, Method a) Rt=2.40 min; MS m/z 555 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[CH:17]=1>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:18]2[CH:17]=[C:16]([CH3:15])[CH:21]=[CH:20][N:19]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2c(Cl)cccc2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)ccn1
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3c(Cl)cccc3c(Cl)c2C)c1

Procedure:
The Stille coupled product was prepared according to Procedure E using 2,4,8-trichloro-3-methylquinoline (0.15 g, 0.61 mmol), 4-methyl-2-(tributylstannyl)-pyridine (0.26 g, 0.67 mmol), palladium tetrakistriphenylphosphine (0.070 g, 0.06 mmol) in toluene (1.2 mL) to give 4,8-dichloro-3-methyl-2-(4-methylpyridin-2-yl)quinoline as a light yellow solid. Mass Spectrum (ESI) m/e=303.0 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]4)[C:14]([C:37]([F:40])([F:39])[F:38])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:4].[CH3:41]I>CN(C=O)C>[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[C:15]([N:17]([CH3:41])[CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]4)[C:14]([C:37]([F:40])([F:38])[F:39])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[CH3:4]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(-c4ccc(CC)cc4)ccc3C(F)(F)F)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(-c4ccc(CC)cc4)ccc3C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.1 %

Procedure:
Sodium hydride (0.02 g, 0.86 mmol) was added to a solution of ethyl [(1S)-5-(3-{[6-(4-ethylphenyl)-3-(trifluoromethyl)-2-pyridinyl]amino}propoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 318) (0.21 g, 0.39 mmol) in DMF (2 mL). After stirring at rt for 30 min, MeI (0.05 mL, 6.32 mmol) was added. The mixture was stirred at rt for 18 h, quenched with water (5 mL), and extracted with ether (3×). The combined ether extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The product (0.017 g, 8%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 7.99 (d, 2H), 7.85 (d, 1H), 7.35-7.25 (m, 3H), 7.01 (d, 1H), 6.72 (d, 1H), 6.65 (dd, 1H), 4.15 (q, 2H), 4.00 (t, 2H), 3.73 (t, 2H), 3.47 (qt, 1H), 3.08 (s, 3H), 2.90-2.68 (m, 5H), 2.42-2.30 (m, 2H), 2.15 (qt, 2H), 1.78-1.68 (m, 1H), 1.32-1.26 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][O:11][N:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[CH3:50][C:51]1[N:56]=[CH:55][C:54]([C:57]2([OH:62])[CH2:61][CH2:60][NH:59][CH2:58]2)=[CH:53][CH:52]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([C:14]([N:59]3[CH2:60][CH2:61][C:57]([C:54]4[CH:55]=[N:56][C:51]([CH3:50])=[CH:52][CH:53]=4)([OH:62])[CH2:58]3)=[O:16])=[CH:12][O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(C2(O)CCNC2)cn1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccc(C)nc3)C2)cc1
Yield: 26.4 %

Procedure:
A solution of 3-(4-methoxyphenyl)isoxazole-4-carboxylic acid (7 mg, 0.03 mmol), N-ethyl-N-isopropylpropan-2-amine (16 μL, 0.09 mmol, 3 equ.) and TBTU (12 mg, 0.036 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-(6-methylpyridin-3-yl)pyrrolidin-3-ol dihydrochloride (8 mg, 0.03 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (3 mg). MS (ESI, pos. ion) m/z: calcd for C21H21N3O4: 379.1532, found 379.1529.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH2:23][CH3:24])[CH:4]=1.[OH:25][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:23]([O:22][C:5]1[CH:4]=[C:3]([CH:21]=[CH:20][C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[O:12][C:13]=1[CH3:14])[CH2:2][O:25][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]=1)[CH3:24]
Reactant: CCOc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a mixture of 4-(4-chloromethyl-2-ethoxyphenoxy)methyl-5-methyl-2-(2-furyl)-1,3-oxazole (0.56 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.25 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.06 g) at room temperature. After stirring the reaction mixture at room temperature for 30 min, the mixture was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-[(3-ethoxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (0.56 g, yield 86%) from a fraction eluted with tetrahydrofuran-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 149-150° C.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][C:8]([F:13])=[C:7]([Cl:14])[N:6]=1.Cl>O1CCOCC1>[Cl:14][C:7]1[N:6]=[C:5]([CH2:4][C:3]([OH:15])=[O:2])[C:10]([C:11]#[N:12])=[CH:9][C:8]=1[F:13]
Reactant: COC(=O)Cc1nc(Cl)c(F)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc(F)c(Cl)nc1CC(=O)O
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A mixture of (6-chloro-3-cyano-5-fluoro-pyridin-2-yl)-acetic acid methyl ester (9.36 g, 40.9 mmol), as prepared in the previous step, 4.0 M HCl (aq) (256 mL) and dioxane (51 mL) was vigorously stirred at 65° C. for 2 h. The homogeneous amber solution was then allowed to cool to rt, extracted with DCM (3×100 mL), dried (Na2SO4) and concentrated under reduced pressure at 45° C. to provide the title compound as a clear, dark amber oil (7.40 g, 84%). 1H-NMR (300 MHz, CDCl3) δ 7.75 (d, 1H), 4.11 (s, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.P(OCC1C=CC=CC=1)(OCC1C=CC=CC=1)OCC1C=CC=CC=1.[CH2:37]([NH2:39])[CH3:38]>O>[CH2:37]([NH:39][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH3:38]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCN
Agent: c1ccc(COP(OCc2ccccc2)OCc2ccccc2)cc1
Solvent: O
Product: CCNc1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
288 parts of β-naphthol, 5 parts of tribenzyl phosphite and 115 parts of ethylamine gas are heated at 230° C in a pressure autoclave for 10 hours. The pressure is 35 atmospheres. The mixture is added to 2,000 parts of water and the batch is stirred for 30 minutes at 70° - 80° C. The lower oily phase is separated off and distilled. 321 parts of N-ethyl-β-naphthylamine, boiling at 119° - 120° C/0.1 mm Hg are obtained, corresponding to a yield of 94% of theory.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:20])=[C:5]([O:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[C:6]([CH3:9])=[N:7][CH:8]=1)=O.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:15]([C:14]1[CH:13]=[C:12]([CH:19]=[CH:18][CH:17]=1)[CH2:11][O:10][C:5]1[C:4]([CH3:20])=[C:3]([CH2:1][NH:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH:8]=[N:7][C:6]=1[CH3:9])#[N:16]
Reactant: Cc1ncc(C=O)c(C)c1OCc1cccc(C#N)c1
Reactant: N#Cc1ccc(N)cc1
Product: Cc1ncc(CNc2ccc(C#N)cc2)c(C)c1OCc1cccc(C#N)c1
Yield: 42.3 %

Procedure:
The reductive amination of 3-(5-formyl-2,4-dimethyl-pyridin-3-yloxymethyl)-benzonitrile (27) (7.0 g, 26.3 mmol) and 4-aminobenzonitrile (10.2 g, 86.3 mmol), as described in Example 21, gave 4-{[5-(3-cyano-benzyloxy)-4,6-dimethyl-pyridin-3-ylmethyl]-amino}-benzonitrile (32) (4.1 g, 68% yield) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][CH2:5]2.[Cl:14][S:15](O)(=[O:17])=[O:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:15]([Cl:14])(=[O:17])=[O:16])[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][CH2:5]2
Reactant: CC(=O)N1CCc2cc(Br)ccc21
Reactant: O=S(=O)(O)Cl
Product: CC(=O)N1CCc2cc(Br)c(S(=O)(=O)Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 5-bromo-N-acetylindoline 122.86 g (0.51 mol) cooled in an ice bath was added chlorosulfonic acid, 116.52 g (2.6 moles) very cautiously. The mixture was stirred for about 30 minutes at 0° C. and then allowed to warm to room temperature. The mixture was then heated slowly to about 70°-90° C. overnight. After cooling, the cold solution was slowly added to ice and the solids collected by suction filtration, washed several times with water and allowed to dry overnight. The product was recrystallized from chloroform to give 72.5 g (42% by weight yield) of 5-bromo-6-chlorosulfonyl-N-acetylindoline.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11](O)=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].CN1CCNCC1[Al+]C1CNCCN1C.CCOCC>O1CCCC1>[C:1]([NH:8][C@@H:9]([CH:11]=[O:12])[CH3:10])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN1CCNCC1[Al+]C1CNCCN1C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](C=O)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
N-Boc-D-alanine is dissolved in tetrahydrofuran and stirred at 0° C. under argon. Bis(N-methylpiperazinyl)aluminum hydride is added and the reaction mixture is heated to reflux overnight. Ether is then added, and the excess hydride is quenched with saturated NaCl. The aqueous phase is separated and extracted with ether. The combined organic phases are washed with 2M NaOH, 2M HCl and saturated NaCl. The solution is dried over Na2SO4 and evaporated to yield N-Boc-D-alaninal.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8]>C(O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[CH:8]=[CH:7][C:6]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]
Reactant: CCNCC
Reactant: C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)C=CN(CC)CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A solution of 14.6 g of diethylamine (0.2 m) in 100 ml of ethyl alcohol was added dropwise to a stirred solution of 19.6 g of ethyl propiolate (0.2 m) in 150 ml ethyl alcohol at room temperature. The exothermic reaction mixture was stirred at room temperature for 31/2 hours. The solvent was removed and the residue distilled through a short Vigreux column (boiling point 88° C./6 mm) to give 29.83 g (87 percent) of ethyl 3-(diethylamino)acrylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:53][C:54]1[CH:55]=[CH:56][C:57]([C:60](O)=[O:61])=[N:58][CH:59]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:60]([C:57]3[CH:56]=[CH:55][C:54]([Cl:53])=[CH:59][N:58]=3)=[O:61])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(=O)c3ccc(Cl)cn3)cc2)COC1(C)C
Temperature: 50 °C
Yield: 91.5 %

Procedure:
To a stirred suspension of (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (150 mg, example 14 (b)) in THF (4 ml) were added sequentially N-methylmorpholine (0.21 ml), TBTU (301 mg) and 5-chloro-2-pyridinecarboxylic acid (111 mg, CAS 86873-60-1) and the mixture was heated at 50° C. for 18 h. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-(2-{4-[(5-chloro-pyridine-2-carbonyl)-amino]-phenyl}-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (197 mg, 91%) as a white solid. MS (ISP): 484.3 ([{37Cl}M+Na]+), 482.3 ([{35Cl}M+Na]+), 462.4 ([{37Cl}M+H]+), 460.5 ([{35Cl}M+H]+), 406.4 ([{37Cl}M+H—C4H8]+), 404.3 ([{35Cl}M+H—C4H8]+).