Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH2:24][OH:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[C:12](=[N:21]O)[CH:11]=2)=[CH:6][CH:5]=1)[CH3:2].[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH3:37])([CH3:36])[C:28]1=[CH2:38]>C(O)C>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]3[O:20][C:28]4([C:29]([CH3:37])([CH3:36])[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:27]4[CH3:26])[CH:38]=[N:21][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1)[CH2:23][CH2:24][OH:25])[CH3:2]
Reactant: CCN(CCO)c1ccc(C2=CC(=NO)C(=O)c3ccccc32)cc1
Reactant: C=C1N(C)c2ccccc2C1(C)C
Solvent: CCO
Product: CCN(CCO)c1ccc(-c2cc3c(c4ccccc24)OC2(C=N3)N(C)c3ccccc3C2(C)C)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A suspension of 4-(4-(ethyl(2-hydroxyethyl)amino)phenyl)-2-(hydroxyimino)naphthalen-1(2H)-one (4.0 g, 11.89 mmol) in ethanol (100 ml) was treated with 1,3,3-trimethyl-2-methyleneindoline (2.68 g, 15.46 mmol) in one portion and heated to 100° C. in a sealed tube for 4 hrs. The mixture was then cooled to RT and left to stand overnight. The resulting suspension was evaporated in vacuo to approx 25 ml total volume, MeOH added (25 ml) and the mixture stored in the freezer for 3 hrs. After this time the product was collected by filtration and washed with a little methanol to give the product, 2-(ethyl(4-(1,3,3-trimethylspiro[indoline-2,2′-naphtho[1,2-b][1,4]oxazine]-6′yl)phenyl)amino)ethanol, as pale green fibres (4.15 g, 71%). Analysis of the product by 1H NMR gave a spectrum consistent with the structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][NH:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=2)[C:14]([CH3:22])=[CH:13]1.C([O-])([O-])=O.[K+].[K+].[CH2:29]([N:33]=[C:34]=[O:35])[CH2:30][CH2:31][CH3:32]>O1CCCC1>[CH2:29]([NH:33][C:34](=[O:35])[O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([NH:11][CH2:10][CH2:9][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1])[CH:13]=[C:14]2[CH3:22])[CH2:30][CH2:31][CH3:32]
Reactant: Cc1cn(NCCCc2ccncc2F)c2ccc(O)cc12
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCNC(=O)Oc1ccc2c(c1)c(C)cn2NCCCc1ccncc1F
Reaction time: 15 h

Procedure:
To a stirred solution consisting of 1-[(3-fluoro-4-pyridinyl)propylamino]-3-methyl-1H-indol-5-ol (2.10 g) and tetrahydrofuran (47 ml) was added milled K2CO3 (1.02 g) followed by dropwise addition of butyl isocyanate (0.87 ml) at room temperature under nitrogen. Stirring was continued for 15 hours, at which time the reaction mixture was filtered through a pad of celite and the solids washed with EtOAc. Concentration afforded the crude product. Purification via flash column chromatography (silica gel, ether) afforded 2.3 g of the desired product as an oil. The product was crystallized from ether/pentane, m.p. 83°-84° C.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])[CH3:7].[CH3:18]O>ClCCl>[CH2:6]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O:13][CH3:18])=[O:12])[CH3:7]
Reactant: CO
Reactant: CCOc1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOc1ccccc1C(=O)OC

Procedure:
Concentrated sulphuric acid (0.5 ml) was added to a solution of 2-ethoxybenzoic acid (50 9, 0.301 mol) in methanol (500 ml) and the resulting mixture heated under reflux for 70 hours, then evaporated under reduced pressure to give an oil which was dissolved in dichloromethane (300 ml). This solution was washed successively with water (150 ml), aqueous sodium bicarbonate solution (150 ml) and water (150 ml), then evaporated under reduced pressure to give the title compound (49.7 a) as an oil. δ (CDCl3): 1.44 (3H,t), 3.90 (3H,s), 4.12 (2H,q), 6.95 (2H,m), 7.44 (1H,t),7.78 (1H,d).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].I[C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>[Cu]>[NH2:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[S:1][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1ccccc1I
Reactant: Nc1ccc(C(=O)O)cc1S
Agent: [Cu]
Product: Nc1ccc(C(=O)O)cc1Sc1ccccc1C(=O)O

Procedure:
Reflux a mixture of 200 ml of the 50% potassium hydroxide solution of Step A, 24.15 gm (97 mmoles) of o-iodobenzoic acid and 7.5 gm of copper metal powder for 11/2 hours. Cool the mixture and filter. Dilute the filtrate to twice its volume with water and acidify. Separate the solids by filtration, wash well with water and air dry.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]2)[N:6]=1.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=1B(O)O>>[NH2:33][C:4]1[S:3][C:2]([C:43]2[C:44]([F:48])=[CH:45][CH:46]=[CH:47][C:42]=2[Cl:41])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]1)=[O:32]
Reactant: OB(O)c1c(F)cccc1Cl
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4c(F)cccc4Cl)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-6-fluorophenyl)boronic acid gave 280. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.89 (s, 1H), 7.61-7.46 (m, 4H), 7.40 (ddd, J=9.6, 8.2, 1.4 Hz, 1H), 5.06 (t, J=5.2 Hz, 1H), 3.68 (d, J=2.8 Hz, 5H), 3.33-3.17 (m, 2H), 2.82 (s, 3H), 1.66-1.49 (m, 4H). LCMS (ES+) m/z 495 (M+1).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[O:12][C:13](=[O:31])/[C:14](=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Br:30])=[CH:19][CH:18]=2)/[N:15]=1)(=O)C.Cl.[CH2:33]([O:35][C:36](=[O:39])[CH2:37][NH2:38])[CH3:34]>C(Cl)Cl>[Br:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][C:20]1[CH:21]=[CH:22][C:17](/[CH:16]=[C:14](\[NH:15][C:11](=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[OH:4])/[C:13]([NH:38][CH2:37][C:36]([O:35][CH2:33][CH3:34])=[O:39])=[O:31])=[CH:18][CH:19]=1
Reactant: CCOC(=O)CN
Reactant: CC(=O)Oc1ccccc1C1=N/C(=C\c2ccc(Oc3ccccc3Br)cc2)C(=O)O1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)/C(=C/c1ccc(Oc2ccccc2Br)cc1)NC(=O)c1ccccc1O
Temperature: 60 °C

Procedure:
A portion of 2-{(4Z)-4-[4-(2-bromophenoxy)benzylidene]-5-oxo-4,5-dihydro-1,3-oxazol-2-yl}phenyl acetate (0.10 g, 0.229 mmol), prepared as described above, is suspended in DCM (10 mL) and treated with glycine ethyl ester hydrochloride (67 m g, 0.48 mmol). The reaction is heated to 60° C. for 4 hours and then concentrated. The resulting solid is triturated with EtOAc to provide ethyl N-{(2Z)-3-[4-(2-bromophenoxy)phenyl]-2-[(2-hydroxybenzoyl)amino]prop-2-enoyl}glycinate, which is subsequently suspended in 1N NaOH (1 mL) and ethanol (1 mL) and stirred at 25° C. for 3 hours. The ethanol is removed and several drops of concentrated HCl added and a precipitate is formed. Filtration afforded 65 mg of N-{(2Z)-3-[4-(2-bromophenoxy)phenyl]-2-[(2-hydroxybenzoyl)amino]prop-2-enoyl}glycine.
Reaction SMILES: [OH:1][CH:2]([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[C:3]#[CH:4].[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1>>[C:13]([O:1][CH:2]([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[C:3]#[CH:4])(=[O:15])[CH3:14]
Reactant: C#CC(O)COC1CCCCO1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C#CC(COC1CCCCO1)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
3-Hydroxy-4-(tetrahydro-2-pyranyloxy)-butyne (8.0 g, 0.047 mole) was mixed with acetic anhydride (10 g, 0.098 mole) and pyridine (8 g, 0.098 mole). The solution was stirred at room temperature for 1 hour and then extracted with ethyl acetate. The extract was sequentially washed with 10% hydrochloric acid (10 ml×5), saturated sodium bicarbonate aqueous solution (10 ml×5) and water (50 ml×3). The extract was dried over anhydrous magnesium sulfate, concentrated and separated by silica gel chromatography, eluted with n-hexane/ethyl acetate (5:1) to give colorless oil (9.0 g, 90%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: ClCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC1(C)OB(c2cnn(Cc3ccncc3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 899.8 %

Procedure:
A mixture of 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (750 mg, 0.387 mmol), 4-Chloromethyl-pyridine (740 mg, 0.581 mmol) and cesium carbonate (3.77 g, 1.16 mmol) was dissolved in acetonitrile (15 mL) was stirred overnight at room temperature. Stirring continued for 5 hrs at 60° C. and the reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (100% Ethyl acetate-4% 2M NH3 in MeOH/CH2Cl2) provided the title compound (993 mg, 90%). 1H NMR (300 MHz, CDCl3): δ 8.59-8.57 (m, 2H), 7.87 (s, 1H), 7.76 (s, 1H), 7.07-7.05 (m, 2H), 5.35 (s, 2H), 1.33 (s, 12H).
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11]([CH3:20])=[C:10]2[CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11]([CH3:20])=[C:10]2[CH2:21][C:22]([CH3:26])([CH3:27])[C:23]([OH:25])=[O:24])=[CH:28][CH:29]=1
Reactant: COc1ccc2c(c1)c(C)c(CC(C)(C)C(=O)O)n2Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)c(C)c(CC(C)(C)C(=O)O)n2Cc1ccc(N)cc1

Procedure:
500 mg of the product of Step 1 was dissolved in 35 ml of absolute ethanol and 50 mg of 10% palladium on carbon catalyst added. The suspension was hydrogenated at 50 psi until consumption of 2 mole equivalents of hydrogen occurred. The catalyst was removed by filtration and the title compound was isolated by vacuum distilation of the solvent (489 mg).
Reaction SMILES: [NH2:1][OH:2].[CH2:3]([N:11]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:12][CH2:13][C:14](OCC)=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>C(OCC)C>[OH:2][NH:1][C:14](=[O:15])[CH2:13][CH2:12][N:11]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20]
Reactant: CCOC(=O)CCN(CCc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(CCC(=O)NO)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
Freshly prepared hydroxylamine reagent (20 mL; 20 mmol) was added to ethyl 3-[(phenethyl)-(4-methoxy-benzenesulfonyl)-amino]-propionate (3.30 g; 9.1 mmol) and the resulting mixture stirred for 18 h at room temperature. The mixture was poured into 1 N HCl (100 mL) and extracted with CH2Cl2 (2×100 mL). The combined extracts were washed with saturated aqueous NaCl (1×100 mL), dried over MgSO4, and evaporated under reduced pressure to give a crude gum. Trituration with diethyl ether afforded 2.23 g (65%) of the title compound as an off-white solid. 300 MHz 1H-NMR (DMSO-d6): δ 2.23 (t, 2H), 2.74 (m, 2H), 3.23 (m, 2H), 3.34 (m, 2H), 3.83 (s, 3H), 7.11 (d, 2H), 7.15-7.34 (m, 5H), 7.72 (d, 2H), 8.78 (s, 1H), 10.50 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:15][OH:16])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:18].[H-].[Na+].OS([O-])(=O)=O.[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:15][O:16][CH3:18])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(CO)CCCN(C(=O)OC(C)(C)C)C1
Reactant: CI
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCC1(C)CCCN(C(=O)OC(C)(C)C)C1
Yield: 64.2 %

Procedure:
A solution of 0.37 g (1.60 mmol) of (rac)-3-hydroxymethyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (intermediate 30B) and 0.20 ml (3.20 mmol) of iodomethane in 15 ml of DMF was treated at 0° C. with 0.08 g (1.92 mmol) of NaH (55% in oil). The reaction was stirred for 2 h at 0° C., neutralized with cold aqueous 10% KHSO4 and extracted with Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane/EtOAc 95:5) to yield 0.25 g (64%) of the title compound as colorless liquid. MS: 244.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:11]=3[O:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.CN(C(ON1N=[N:44][C:39]2C=[CH:41][CH:42]=[CH:43][C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.N1CCCCC1>C(OCC)(=O)C.CN(C=O)C>[F:28][C:23]1[CH:22]=[C:21]([C:9]2([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([N:44]4[CH2:41][CH2:42][CH2:43][CH2:38][CH2:39]4)=[O:20])=[CH:17][C:11]=3[O:10]2)[CH:26]=[C:25]([F:27])[CH:24]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1ccc2c(c1)OC(c1cc(F)cc(F)c1)(c1cc(F)cc(F)c1)O2
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCNCC1
Product: O=C(c1ccc2c(c1)OC(c1cc(F)cc(F)c1)(c1cc(F)cc(F)c1)O2)N1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
96 mg 2,2-bis-(3,5-difluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid, 93 mg HBTU, 1 mL DMF and 50 mg N-methylmorpholine were stirred at room temperature. After 5 min 21 mg piperidine were added and the mixture stirred at room temperature for 24 h. The mixture was diluted with ethyl acetate and washed twice with water. Evaporation of the solvents and purification on silica gel afforded 111 mg of a white foam, MS: 457 ([M]+).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[CH3:5][C:6]([CH3:10])([CH3:9])[CH:7]=[O:8].C(N(CC)CC)C>CCOC(C)=O>[CH3:5][C:6]([CH3:10])([CH3:9])[CH:7]([OH:8])[CH2:4][N+:1]([O-:3])=[O:2]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)C(O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.3 %

Procedure:
A mixture of nitromethane (5.87 g, 68.1 mmol), 2,2-dimethyl-propionaldehyde (5.4 g, 88.6 mmol), and triethylamine (689 mg, 6.8 mmol) was stirred at room temperature for two days; then the reaction mixture was diluted with EtOAc, washed with diluted HCl aqueous solution, and saturated NaCl aqueous solution respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give a clear oil, the title product (7.35 g); The title product, 1H NMR (200 MHz, CDCl3): δ (ppm)=4.52 (dd, 1H, J=2.4 Hz, 12.6 Hz), 4.36 (dd, 1H, J=10.0 Hz, 12.6 Hz), 4.01 (m, 1H), 2.42 (d, 1H, J=4.4 Hz), 0.98 (s, 9H).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH2:9]1.O=[C:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:42][CH2:41][CH2:40][C:39]2=[O:43])[CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>C(#N)C>[O:43]=[C:39]1[CH2:40][CH2:41][CH2:42][N:38]1[CH:35]1[CH2:34][CH2:33][CH:32]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]([F:28])([F:27])[F:29])[CH:24]=4)[N:19]=[CH:18][N:17]=3)[CH2:11]2)[CH2:37][CH2:36]1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: O=C1CCC(N2CCCC2=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(N3CCCC3=O)CC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide TFA salt (100 mg, 0.22 mmol) from example 1, step G, and 1-(4-oxocyclohexyl)pyrrolidin-2-one (40.5 mg, 0.22 mmol) from above step B, Sodium triacetoxyborohydride (138 mg, 0.64 mmol), were taken in acetonitrile and stirred for 24 h at room temperature. The mixture was treated with MeOH and concentrated under vacuum. The residue was purified by preparative TLC (nBuOH/aq NH4OH 4:1) and reverse phase HPLC to give the title compound as a white solid. ESI-MS (m/z): Calcd. for C24H29F3N6O2: 490.23. found: 491.23 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]2[C:17]=1[CH2:18][CH2:19][NH:20][CH:21]2[CH3:28]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:16]=4[O:15][CH3:14])[CH:21]3[CH3:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ccc2c(c1OC)CCNC2C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: COc1ccc2c(c1OC)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5,6-Dimethoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]=[N+:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][N:12]2[CH2:13][CH:14]=[CH:15][CH2:16][CH2:17]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(N=[N+]1C=CC=CC1)Nc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(F)cc1)NN1CC=CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of N-[[(4-fluorophenyl)carbamoyl]-imino]pyridinium ylide (1.04 g) and sodium borohydride (2.55 g) in ethanol (100 ml) was stirred at ambient temperature for 16 hours. Excess of sodium borohydride was decomposed with water, and the resulting mixture was evaporated. The residue was extracted with chloroform (20 ml×3). The combined organic extract was washed with water, dried over magnesium sulfate and evaporated to give crystalls. Recrystallization from diisopropyl ether gave N-[[(4-fluorophenyl)-carbamoyl]amino]-1,2,3,6-tetrahydropyridine (0.60 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:25])[C@H:12]([CH2:14][CH2:15][CH2:16][NH:17]C(OC(C)(C)C)=O)[NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[C:30]1([CH2:36][CH:37]=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([BH3-])#N.[Na+]>CO>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:25])[C@H:12]([CH2:14][CH2:15][CH2:16][NH2:17])[NH:13][CH2:37][CH2:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)NCCCc1ccccc1
Reactant: O=CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NCCC[C@H](NCCc1ccccc1)C(=O)NCCCc1ccccc1
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
A cold solution (0° C.) of the above amine (3 g, 8.6 mmol), in methanol (20 ml), was treated sequentially with acetic acid (345 μl, 6 mmol) and phenylacetaldehyde (1.2 ml, 10 mmol). Then a solution of sodium cyanoborohydride (2.7 g, 43 mmol) in methanol (10 ml) was added to the mixture slowly. The reaction was stirred for additional 30 minutes and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate, and purified by chromatography (silica gel, hexane/ethyl acetate) to afford Nα-(phenethyl)ornithine 3-phenylpropylamide (2.64 g): 1H NMR (400 MHz, CD3OD) δ1.4 (s, 9H), 1.45-1.8 (m, 6H), 2.6 (t, J=6.4 Hz, 2H), 2.65-2.8 (m, 4H), 3.02-3.2 (m, 5H), and 7.1-7.3 (m, 10H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22](O)=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.O.C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[N:9]=1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1ccc(I)cc1N
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: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(I)ccc2[nH]1
Temperature: 1 °C
Yield: 84.3 %

Procedure:
To a dry 1000 mL round bottom flask under Nitrogen, is added 4-Iodo-benzene-1,2-diamine (45 g), (S)-Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (41.39 g) and THF (450 ml). The reaction mixture is stirred until complete dissolution then cool to 0-2° C. Diisopropylethylamine (50.17 ml) is added dropwise to control the exotherm then HATU (80.38 g) is added in one portion. The reaction mixture is stirred in an ice bath for 3 hours and follows by HPLC to monitor completion of reaction. To this solution are added 500 ml of water then 500 ml of ethyl acetate. The aqueous phase extracted twice with ethyl acetate. The organic phases are combined and evaporated half. To the organic phase is added 450 ml of acetic acid and the mixture is evaporated to 300 ml. This procedure is repeated 3 times for a residual of −470 ml, and the mixture is then heated at 50° C. over night. Toluene (200 ml) is added and evaporated to a small residue (repeat 6 times). To this solution is added 450 ml of ethyl acetate. The organic phase is washed with saturated sodium carbonate, dried over sodium sulfate, filtered and evaporated to dryness. The residue is purified on a pad of silica using 25% ethyl acetate/hexane mixture to give compound (67 g) as a beige powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:20][CH2:21][C@@:22]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[C:11](=O)[O:12]C2C=CC=CC=2)[CH3:9])=[CH:4][CH:3]=1.CN1C(=O)CCC1.[OH-].[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:20][CH2:21][C@:22]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:34][C:11]2=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N(CC[C@](O)(CC(C)(C)O)c1ccccc1)C(=O)Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A flask is charged with phenyl (S)-1-(4-bromophenyl)ethyl((S)-3,5-dihydroxy-5-methyl-3-phenylhexyl)carbamate (25.0 g, 47.5 mmol) and NMP (125 mL). The resultant solution is treated with 50 wt. % aqueous KOH (12.5 mL), stirred at 25° C. for 1 hour, and treated with water (250 mL). The resultant slurry is stirred at 25° C. for 1 hour, and the solids collected by filtration. The solids are then washed with water and heptane, and dried under vacuum at 50° C. for 18 hours to provide 6 as a white solid. Yield: 19.7 g, 95.1%; 99.1%. purity by weight.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]([O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([CH3:14])[CH3:13]>>[CH:12]([O:15][C:16]1[CH:21]=[C:20]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH:19]=[CH:18][CH:17]=1)([CH3:14])[CH3:13]
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Reactant: CC(C)Oc1cccc(B(O)O)c1
Product: Cc1cc([N+](=O)[O-])cnc1-c1cccc(OC(C)C)c1
Yield: 82 %

Procedure:
Obtained (1.03 g, yield 82%) following the procedure described in Intermediate 27, starting with 2-bromo-3-methyl-5-nitropyridine (4.61 mmol, 1.0 g), 3-isopropoxyphenylboronic acid (4.61 mmol, 0.83 g).