Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=O)[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1.CN(C(ON1N=[N:34][C:29]2[CH:30]=[CH:31][CH:32]=[N:33][C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.NC1C=NC=CC=1>CN(C=O)C>[N:33]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:34][C:15]([C:10]2[CH:11]=[CH:12][C:13]3[CH:14]=[C:6]4[C:5](=[O:18])[NH:4][CH2:3][CH:2]([CH3:1])[N:7]4[C:8]=3[CH:9]=2)=[O:17])[CH:28]=1
Reactant: CC1CNC(=O)c2cc3ccc(C(=O)O)cc3n21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CNC(=O)c2cc3ccc(C(=O)Nc4cccnc4)cc3n21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
To a solution of 4-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-7-carboxylic acid (step f) (20 mg, 0.08 mmol) in 1 mL of DMF was added HATU (34.3 mg, 0.082 mmol), HOAt (6, 0.04 mmol) and diisopropylethylamine (29 uL, 0.164 mmol). After 15 min, 3-amino-pyridine in 1 mL of DMF was added. The mixture was stirred at room temperature for 48 h. The reaction was extracted with EtOAc several times, washed with water and brine. The combined organics were dried over MgSO4, filtered, and concentrated in vacuum. Purification by silica gel chromatography gave 23 mg of 4-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-7-carboxylic acid pyridin-3-ylamide 87% as a white solid. ESI-MS m/z 321.34 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH:17]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH2:17][N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=3[CH3:19])[CH2:28][CH2:29]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1cccs1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4cccs4)n(C(C)(C)C)n3)CC2)c(C)c1

Procedure:
79 mg (87%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg, 0.191 mmol), 1-(2,4-dimethylphenyl)piperazine (36 mg, 0.191 mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)3 (121 mg, 0.573 mmol).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(OCC)(=O)C.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.COCCOC>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C)ccc1Br
Reactant: OB(O)c1ccncc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)ccc1-c1ccncc1
Yield: 48.5 %

Procedure:
A mixture of methyl 2-bromo-5-methylbenzoate (5.2 g), pyridine-4-boronic acid (4.2 g), sodium carbonate (4.8 g), tetrakis(triphenylphosphine)palladium(0) (1.3 g), water (10 mL) and DME (50 mL) was heated under reflux overnight under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, and filtered through silica gel. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.5 g).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:31][CH3:32])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH:21][CH2:22][C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH2:24])[CH:9]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:43](Cl)([O:45]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:31][CH3:32])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]2[CH2:22][C@@H:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:24][C:43]2=[O:45])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNC[C@H](N)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C[C@@H](c2ccccc2)NC1=O
Reaction time: 0.75 h

Procedure:
A solution of (1R)—N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1-phenylethane-1,2-diamine (96.0 mg, 0.22 mmol) in CH2Cl2 (15 mL) was cooled to 0° C. and DIPEA (230 μL, 1.32 mmol) was added followed by triphosgene (32.6 mg, 0.11 mmol). After 45 minutes, the reaction was poured into saturated NaHCO3 (25 mL). The mixture was extracted with EtOAc (75 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 10 to 60% EtOAc/hexanes afforded (4R)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-phenylimidazolidin-2-one. The minor enantiomer was removed by chiral HPLC using an AD chiral column and 15% IPA/heptanes to afford enantiomerically pure product. Rf=0.16 (40% EtOAc/hexanes). LCMS=469.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) (atropisomers present in 1:1 ratio, doubling of some peaks observed) δ 7.65 (m, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.21-7.36 (m, 71-1), 6.87-6.94 (m, 2H), 4.65-4.77 (m, 21-1), 4.10-4.49 (m, 2H), 3.71 & 3.72 (2 singlets, 3H), 3.49-3.53 (m, 1H), 2.94-2.97 (m, 1H), 2.87 (m, 1H), 1.19-1.24 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:25]2[CH2:26][CH2:27][CH:22]([C:19]3[CH:18]=[CH:17][N:16]=[CH:21][CH:20]=3)[CH2:23][CH2:24]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: c1cc(C2CCNCC2)ccn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CN2CCC(c3ccncc3)CC2)CC1
Yield: 37.8 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(formyl)piperidine (2.59 g) and 4-(4-pyridyl)piperidine (1.97 g) in methanol/acetic acid (99:1) was added sodium cyanoborohydride (2.29 g) portionwise over 30 minutes and the resultant suspension stirred at ambient temperature for 3 hours. The suspension was quenched by addition of saturated aqueous sodium bicarbonate solution and the resulting mixture extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 5% methanol in dichloromethane to give 1-tert-butoxycarbonyl-4-[4-(4-pyridyl)-1-piperidylmethyl]piperidine (1.65 g) as a solid.
Reaction SMILES: N[C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([Br:13])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(O)C>[Br:13][C:5]1[C:6]2[CH2:7][C:8]([CH3:12])([CH3:11])[O:9][C:10]=2[CH:2]=[CH:3][CH:4]=1
Reactant: CC1(C)Cc2c(Br)ccc(N)c2O1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)Cc2c(Br)cccc2O1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
A stirred solution of 12.3 grams (0.051 mole) of 7-amino-4-bromo-2,3-dihydro-2,2-dimethylbenzofuran and 30 mL of toluene in 200 mL of ethanol was cooled in an ice-bath, and 5.6 mL (0.102 mole) of concentrated sulfuric acid was added slowly, followed by 5.6 grams (0.082 mole) of sodium nitrite. Upon completion of addition, the ice-bath was removed, and the reaction mixture was warmed to 50° C. The reaction mixture temperature was then brought to about 75° C., where it was stirred for 30 minutes. After this time the reaction mixture was heated at reflux for one hour and then was poured into 200 mL of water. The mixture was extracted with two 150 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.6 grams of 4-bromo-2,3-dihydro-2,2-dimethylbenzofuran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[N:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1ccc(CO)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(Br)cc2)cn1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
4-Bromophenol (1.37 g, 7.90 mmol) was added to a solution of (6-methoxypyridin-3-yl)methanol (1.0 g, 7.16 mmol) in THF (100 mL). Triphenylphosphine (1.88 g, 7.19 mmol) was added followed by triethylamine (0.727 g, 7.19 mmol). The resulting solution was cooled to 0° C. and DIAD (1.45 g, 7.19 mmol) was added by drop-wise addition and was maintained at 0° C. for 30 minutes, then warmed to room temperature and stirred for two days. The reaction was quenched by addition of water and extracted with ether (2×100 mL). The organic layer was washed with water (2×100 mL) then brine (1×100 mL), dried (MgSO4), filtered and concentrated to give a yellow oil. The crude material was purified by flash column chromatography on a Biotage SNAP cartridge Kp-sil 100g column (hexanes/ethyl acetate 9:1) to give a white solid. Mass/Yield—1.78 g/84% TLC (hexanes/ethyl acetate=8:2) Rf=0.12, UV active. LCMS MS ES+294.4/296.4. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.93 (s, 3 H) 4.93 (s, 2 H) 6.72-6.78 (m, 1 H) 6.81-6.86 (m, 2 H) 7.33-7.42 (m, 2 H) 7.58-7.65 (m, 1 H) 8.18 (s, 1 H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12][N:13]=2)[CH:6]=[CH:7][CH:8]=1.Cl.N1C=CC=CC=1.[OH-].[Na+]>O>[C:14]1([N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(-c2nccn2-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: Oc1cccc(-c2nccn2-c2ccccc2)c1
Temperature: 200 °C

Procedure:
To a 500 mL round bottom flask was added 2-(3-methoxyphenyl)-1-phenyl-1H-imidazole (6.52 g, 26.0 mmol) and pyridine hydrochloride (24.08 g, 208 mmol). The reaction mixture was heated to 200° C. for 3 h under nitrogen. The reaction mixture was cooled to room temperature and the solid was added to water. The aqueous mixture was adjusted to pH 7 with sodium hydroxide solution. A gray solid was filtered off, washed with water, and dried (5.38 g, 83%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:8][CH2:7][C@@H:6]([N:9]2[C:13]3=[C:14]4[S:20][CH:19]=[CH:18][C:15]4=[N:16][CH:17]=[C:12]3[N:11]=[C:10]2[C@@H:21]([OH:23])[CH3:22])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:40][C:30]1[CH:35]=[CH:34][C:33]([S:36]([O:1][CH2:2][C@H:3]2[CH2:4][CH2:5][C@H:6]([N:9]3[C:13]4=[C:14]5[S:20][CH:19]=[CH:18][C:15]5=[N:16][CH:17]=[C:12]4[N:11]=[C:10]3[C@@H:21]([OH:23])[CH3:22])[CH2:7][O:8]2)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)OC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](n3c([C@H](C)O)nc4cnc5ccsc5c43)CO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a solution of (1S)-1-{1-[(3S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol (48.0 mg, 0.144 mmol) in methylene chloride (2.09 mL) and pyridine (70.4 μL, 0.871 mmol) was added p-toluenesulfonyl chloride (35.0 mg, 0.184 mmol) and 4-dimethylaminopyridine (1.1 mg, 0.0092 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with methanol, and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product as white solid (42 mg, 60%). LCMS calculated for C23H26N3O5S2 (M+H)+: m/z=488.1. Found: 488.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[OH:45][CH2:46][C@H:47]1[CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][C:54]=2[CH2:57][CH2:58][C:59]([CH3:62])([OH:61])[CH3:60])[C@H:49]([CH3:63])[NH:48]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:48]1[C@@H:47]([CH2:46][OH:45])[CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][C:54]=2[CH2:57][CH2:58][C:59]([OH:61])([CH3:60])[CH3:62])[C@@H:49]1[CH3:63])=[O:11]
Reactant: C[C@@H]1N[C@@H](CO)Cc2c(CCC(C)(C)O)cccc21
Reactant: O=C(O)Cc1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1c2cccc(CCC(C)(C)O)c2C[C@H](CO)N1C(=O)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.9 %

Procedure:
Dissolve 2-(2-chlorophenyl)acetic acid (96.8 mg, 0.56 mmol) and O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (200 mg, 0.52 mmol) in dichloromethane (2 mL). Add diisopropylethylamine (183 μL, 1.05 mmol). Stir at ambient temperature for 20 min. Add this reaction mixture to a solution of 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol (92 mg, 0.35 mol) in dichloromethane (0.4 mL). Rinse with dichloromethane (1 mL) and stir at ambient temperature for 3.5 hours. Dilute the reaction mixture with water and stir. Extract with dichloromethane and dry the extracts over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 0-60%) to give a residue. Purify the residue by silica gel chromatography, eluting with 10% (2N ammonia in methanol): dichloromethane to give the title compound as a white foam (78 mg, 0.19 mmol). MS (m/z): 416.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:9](I)[CH3:10].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C@:19]2([CH2:43][C:44]([OH:47])([CH3:46])[CH3:45])[O:24][C:23](=[O:25])[N:22]([C@H:26]([C:28]3[CH:33]=[CH:32][C:31](B4OC(C)(C)C(C)(C)O4)=[CH:30][CH:29]=3)[CH3:27])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>>[CH2:9]([N:6]1[C:5](=[O:8])[CH:4]=[CH:3][C:2]([C:31]2[CH:30]=[CH:29][C:28]([C@@H:26]([N:22]3[CH2:21][CH2:20][C@@:19]([C:16]4[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=4)([CH2:43][C:44]([OH:47])([CH3:45])[CH3:46])[O:24][C:23]3=[O:25])[CH3:27])=[CH:33][CH:32]=2)=[CH:7]1)[CH3:10]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reactant: CCI
Reactant: O=c1ccc(Br)c[nH]1
Product: CCn1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccc(F)cc4)OC3=O)cc2)ccc1=O

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 59, using 5-bromopyridin-2(1H)-one and ethyl iodide in Step 1 and (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one in Step 2. LC-MS Method 2 tR=1.205 min, m/z=493.2; 1H NMR (CDCl3) 1.16 (d, 6H), 1.39 (t, 3H), 1.52 (d, 3H), 2.19 (s, 4H), 2.20-2.31 (m, 2H), 2.38-2.50 (m, 1H), 2.90 (m, 1H), 4.04 (m, 2H), 5.69 (m, 1H), 6.66 (d, 1H), 7.00 (m, 4H), 7.18 (d, 2H), 7.30 (m, 2H), 7.41 (s, 1H), 7.51 (d, 1H). Recrystallization from isopropyl acetate following a procedure analogous to that described for Example 37 in Recrystallization Method B afforded a crystalline solid with mp 172-173.6° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:4]=2[O:3]1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH3-][C:22]#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[CH3:13][C:2]1([CH3:1])[CH:6]=[CH:22][C:5]2[C:4](=[CH:10][CH:9]=[C:8]([CH2:11][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:7]=2)[O:3]1
Reactant: CC1(C)Cc2cc(C=O)ccc2O1
Reactant: [BH3-]C#N
Reactant: Nc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CO
Product: CC1(C)C=Cc2cc(CNc3ccccc3)ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111 %

Procedure:
To a solution of 2,3-dihydro-2,2-dimethylbenzofuran-5-carboxaldehyde 14 (250 mg, 1.42 mmol) in MeOH (10 mL) was added aniline (0.14 mL, 1.022 mmol), NaCNBH3 (178 mg, 2.84 mmol) and ZnCl2 (dried in oven) (387 mg, 2.84 mmol). The reaction was stirred at room temperature overnight, and then the solvent was removed by rotary evaporation. 0.1M NaOH was added to the resulting residue, which was extracted with EtOAc (×2). The combined organic layers were dried over MgSO4 and concentrated in vacuum to give 301 mg of the product (84%). 1H NMR (CDCl3): d 7.29-7.22 (m, 3H), 7.17 (d, J=8.0 Hz, 1H), 6.95-6.70 (m, 4H), 4.28 (s, 2H), 3.06 (s, 2H), 1.55 ppm (s, 6H).
Reaction SMILES: [F:1][C:2]([F:35])([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[C@H:11]([C:25]([O-])=[O:26])[C@@:12]([OH:24])([CH2:20][CH2:21][O:22][CH3:23])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(C1(CCCCCC/C=C/[C@H](C([O-])=O)[C@@](O)(CCOC)C(OC(C)(C)C)=O)OCCO1)CCCCCC.[NH2:73][C@@H:74]([CH2:79][C:80]1[CH:85]=[CH:84][C:83]([O:86][CH2:87][CH2:88][CH2:89][CH3:90])=[CH:82][CH:81]=1)[C:75]([O:77][CH3:78])=[O:76]>>[CH2:87]([O:86][C:83]1[CH:82]=[CH:81][C:80]([CH2:79][C@H:74]([NH:73][C:25]([C@@H:11](/[CH:10]=[CH:9]/[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C@@:12]([OH:24])([CH2:20][CH2:21][O:22][CH3:23])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:26])[C:75]([O:77][CH3:78])=[O:76])=[CH:85][CH:84]=1)[C:88]#[C:89][CH3:90]
Reactant: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)[O-])[C@@](O)(CCOC)C(=O)OC(C)(C)C
Reactant: CCCCOc1ccc(C[C@H](N)C(=O)OC)cc1
Agent: CCCCCCCC1(CCCCCC/C=C/[C@H](C(=O)[O-])[C@@](O)(CCOC)C(=O)OC(C)(C)C)OCCO1
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(F)(F)CCCCCCC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)OC)cc1

Procedure:
No. 6804236 was obtained by the synthetic method in Step A-4 (dehydration condensation with 1-[bis(dimethylamino)methyliumyl]-1H-1,2,3-triazolo[4,5-B]pyridine-3-oxide hexafluorophosphate), except that No. 5553644, 1-tert-butyl (2S,3S)-3-((E)-9,9-difluoro-hexadec-1-enyl)-2-hydroxy-2-(2-methoxy-ethyl)-succinate was used instead of No. 6801710, 1-tert-butyl (2S,3S)-3-[(E)-8-(2-heptyl-[1,3]dioxolan-2-yl)-oct-1-enyl]-2-hydroxy-2-(2-methoxy-ethyl)-succinate, and methyl (S)-2-amino-3-(4-butoxy-phenyl)-propionate was used instead of methyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate.
Reaction SMILES: CNC1[S:4][C:5]([S:8](=[O:18])(=[O:17])[N:9]([CH3:16])[CH2:10][C:11]2[O:15][CH:14]=[CH:13][CH:12]=2)=[N:6][N:7]=1.[CH3:19]N=C=O.[CH3:23][NH:24][C:25]([NH:27][CH3:28])=[O:26]>C1(C)C=CC=CC=1>[CH2:10]([N:9]([CH3:16])[S:8]([C:5]1[S:4][C:23]([N:24]([CH3:19])[C:25]([NH:27][CH3:28])=[O:26])=[N:7][N:6]=1)(=[O:18])=[O:17])[C:11]1[O:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNc1nnc(S(=O)(=O)N(C)Cc2ccco2)s1
Reactant: CNC(=O)NC
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)N(C)c1nnc(S(=O)(=O)N(C)Cc2ccco2)s1

Procedure:
To a solution of 3 g. of 2-methylamino-5-[N-methyl-N-furfurylsulfamoyl]-1,3,4-thiadiazole (from Preparation 3) in 50 ml. of toluene was added 1 g. of methyl isocyanate. The reaction mixture was heated at reflux for about 3 hours. The reaction product mixture was cooled and the solid which precipitated was filtered off. The solid weighed about 2.5 g. It was recrystallized from commercial absolute ethanol to give tan crystals weighing about 1 g., and having a melting point of about 131°-132° C. The product was identified by NMR spectrum and elemental analyses as 1-[5-N-furfuryl-N-methylsulfamoyl)-1,3,4-thiadiazol-2-yl]-1,3-dimethylurea.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([N:8]([CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C=O)c1
Reactant: COc1ccc(C(=O)CNCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(C(=O)CN(Cc2ccccc2)Cc2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a solution of 2-benzylamino-1-(4-methoxy-phenyl)-ethanone (12.0 g, 47.0 mmol, see Preparation 60) and 3-methoxy benzaldehyde (6.09 g, 44.8 mmol) in 1,2 DCE (250 ml) was added NaB(OAc)3H. The reaction mixture was stirred at RT overnight. The reaction was poured into sat. NaHCO3 (150 ml) and extracted with CH2Cl2 (3×100 ml). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography (SiO2, gradient elution 20% to 50% EtOAc/hexanes) gave the title product (13.85 g, 36.9 mmol, 83% yield).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)=O.O.[NH2:18]N>C(O)C>[N+:13]([C:9]1[CH:8]=[C:7]([C:5]2[CH:4]=[CH:3][NH:2][N:18]=2)[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: CN(C)/C=C/C(=O)c1cccc([N+](=O)[O-])c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(-c2cc[nH]n2)c1
Reaction time: 5 h
Yield: 100.9 %

Procedure:
2.5 g (11 mmol) of (2E)-3-(dimethylamino)-1-(3-nitrophenyl)prop-2-en-1-one were dissolved in 25 ml of ethanol and 2.3 ml of hydrazine hydrate 98% (46 mmol) were added. The resulting solution was refluxed under stirring for 5 hours. The solvent was then evaporated and the crude was dissolved with dichloromethane and washed with water. The organic layer was dried over sodium sulphate and the solvent removed in vacuo. The residue was then triturated with diisopropylether and collected by filtration, giving 2.1 g of the title compound (98%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[S:9]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10]1.O>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:15]([NH:14][C:11]1[CH:12]=[CH:13][S:9][CH:10]=1)=[O:16]
Reactant: CN1CC(=O)N=C1N
Reactant: O=C=Nc1ccsc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccsc1
Temperature: 75 °C

Procedure:
To a stirred suspension of 2.6 (23 mM) of creatinine in 50 ml of anhydrous DMF was added a solution of 3.0 g (23 mM) of 3-thienyl isocyanate in 25 ml of toluene. The resulting mixture was heated at 75° C. for 4.5 hrs., cooled and added to 150 ml of water. The resulting precipitate was collected and recrystallized from ethyl acetate to give 1.4 g of the above urea as a cream colored solid, m.p. 194°-195° C.