Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[CH3:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O.CN(C=O)C>[CH2:21]([N:20]([C:16]1[S:15][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[N:17]=1)[CH3:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: N#C[S-]
Reactant: CNCc1ccccc1
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)c1nc(=O)c2cccnc2s1
Yield: 48.2 %

Procedure:
The reaction procedure of Example 57 was followed except that 1.757 g (11.2 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride, two droplets of DMF, 891 mg of ammonium thiocyanate, 15 ml of acetone, 1.42 g of N-methylbenzylamine and 10 ml of acetone were used. The resulting crude product was then recrystallized from a mixture of ethanol and ether to obtain 1.53 g of 2-(N-benzyl-N-methylamino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd].C(OCC)(=O)C>[CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([C:32]3[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=3)=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1cnn2c(C3CCCCC3)c(-c3ccc(I)cc3)cnc12
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2ccc(-c3cnc4c(C#N)cnn4c3C3CCCCC3)cc2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 61.3 %

Procedure:
A mixture of 65 mg (0.15 mmol) of 7-cyclohexyl-6-(4-iodo-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile, 45 mg (0.225 mmol, 1.5 equiv) of 4-(methanesulfonyl)phenylboronic acid, 6 mg (0.0075 mmol, 5 mol %) of Pd catalyst, and 95 mg (0.45 mmol, 3 equiv) of potassium phosphate was placed into a carousel tube. After a vacuum and argon cycle, 1,4-dioxane (3 mL) was added, and the resulting mixture was heated at 80° C. under argon for 14 h. Since analysis by LC-MS revealed unreacted starting material still present, 45 mg (0.225 mmol, 1.5 equiv) of 4-(methanesulfonyl)phenylboronic acid, 12 mg (0.015 mmol, 10 mol %) of Pd catalyst, and 95 mg (0.45 mmol, 3 equiv) of potassium phosphate was added and heating was continued for 24 h. The reaction mixture was then diluted with ethyl acetate, filtered through a small pad of Celite, dried over sodium sulfate and evaporated to give a brown residue (crude coupling product), which was chromatographed on silica gel (Biotage; gradient elution 2% to 10% ethyl acetate in dichloromethane) to afford 42 mg (62% yield) of desired 7-cyclohexyl-6-(4′-methanesulfonyl-biphenyl-4-yl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile as indicated by 1H NMR; LC-MS—calcd for C26H24N4O2S [M++H]+: 457.16, found: 457.1.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[C:43](=[O:48])[NH:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[C:43](=[O:48])[NH:42][N:41]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4n[nH]c(=O)n4CCC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4n[nH]c(=O)n4CCC)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-propyl-1H-1,2,4-triazol-5-on-3-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.50 g) was dissolved in dichloromethane (30 ml), and the mixture was cooled to −78° C. To the solution, 3-chloroperbenzoic acid (0.22 g) in dichloromethane solution (5 ml) was added dropwise. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-propyl-1H-1,2,4-triazol-5-on-3-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 66) (0.45 g) as yellow amorphous.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].I[CH3:15].O>CN(C=O)C>[CH3:15][N:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: CI
Reactant: N#Cc1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2cc(C#N)cnc21
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a stirred solution of 1H-Pyrrolo[2,3-b]pyridine-5-carbonitrile (2.88 g, 20.1 mmol) in DMF (40 mL) was added 60% NaH (2.41 g, 60.4 mmol). After 20 minutes, iodomethane was added in one portion (6.3 mL, 101 mmol) and the resulting mixture was stirred overnight. The following day, water was carefully added drop-wise to quench the remaining NaH before additional water was added (50 mL) causing precipitation of the product. Filtration and drying in vacuo afforded 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (3.16 g, 20.1 mmol, 100% yield) which was subsequently used without further purification. ES MS (M+H+)=158.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>O1CCCC1>[N:16]1([S:13]([C:10]2[CH:11]=[CH:12][C:7]([B:21]([OH:26])[OH:22])=[CH:8][CH:9]=2)(=[O:15])=[O:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCCC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(B(O)O)cc1)N1CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
n-Butyllithium (20 mL, 31 mmol) was added dropwise over 30 min to a cooled (−78° C.) solution of 1-[(4-bromophenyl)sulfonyl]pyrrolidine (3.0 g, 10.3 mmol) and triisopropyl borate (7.2 mL, 30.9 mol) in anhydrous tetrahydrofuran (10 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 1 h at −78° C. whereafter the temperature was allowed to reach room temperature over 3 h. Silica gel was added and the solvent was evaporated. Chromatography on a silica gel column using a gradient methylene chloride (100%) to methylene chloride/ethanol, (1:1), gave 1.85 g (70% yield) of the title compound as a white solid: 1H NMR (CD3OD, 400 MHz) δ 7.90 (d, J=7 Hz, 2H), 7.75 (d, J=8 Hz, 2H), 3.21 (m, 4H), 1.72 (m, 4H); 13C NMR (CDCl3/CD3OD (1:1), 100 MHz) δ 136.79, 133.50, 125.48, 47.19, 24.30; MS (ES) m/z 256 (M++1).
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.C1C=[C:26]2[N:28]=N[N:30](O)[C:25]2=[CH:24]C=1.O.CCN=C=NCCCN(C)C.Cl.Cl.NC(C)C#N.CN1CCOCC1>CN(C=O)C>[C:26]([CH:25]([NH:30][C:13](=[O:15])[C@H:12]([N:9]1[C:8](=[O:19])[C:7]2=[CH:20][NH:21][C:5]3[C:6]2=[C:11]([C:2]([F:1])=[CH:3][N:4]=3)[CH2:10]1)[CH:16]([CH3:18])[CH3:17])[CH3:24])#[N:28]
Reactant: On1nnc2ccccc21
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Agent: CC(N)C#N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C#N)NC(=O)[C@@H](C(C)C)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDC hydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL). 2-Aminopropanenitrile hydrochloride (8.23 mg, 0.077 mmol) and 4-methylmorpholine (0.023 mL, 0.206 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. Following reaction, the product was purified by preparative HPLC (10-55% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and lyophilized to afford the title compound as a white solid (11 mg, 62%). 1H NMR (500 MHz, DMSO-d6) δ 1.20-1.26 (m, 3H), 1.32-1.39 (m, 3H), 1.77-1.82 (m, 3H), 2.76-2.84 (m, 1H), 5.06-5.22 (m, 1H), 5.36-5.44 (m, 2H), 5.77 (dd, J=19.0, 2.0 Hz, 1H), 8.38 (dd, J=10.5, 2.0 Hz, 1H), 8.65 (t, J=3.0 Hz, 1H), 9.47 (d, J=2.0 Hz, 1H), 12.78 (br d, J=7.5 Hz, 1H). [M+H] calc'd for C17H18FN5O2, 344; found, 344.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH2:6])[CH3:5].Cl[C:8]1[C:17]2[C:12](=[CH:13][C:14]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][C:9]=1[N+:27]([O-:29])=[O:28].C(N(CC)CC)C>CN1C(=O)CCC1.O>[CH3:26][C:21]1[C:20]([C:14]2[CH:13]=[C:12]3[C:17]([C:8]([NH:6][CH:4]([CH3:5])[CH2:3][O:2][CH3:1])=[C:9]([N+:27]([O-:29])=[O:28])[CH:10]=[N:11]3)=[CH:16][C:15]=2[O:18][CH3:19])=[C:24]([CH3:25])[O:23][N:22]=1
Reactant: COCC(C)N
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: COCC(C)Nc1c([N+](=O)[O-])cnc2cc(-c3c(C)noc3C)c(OC)cc12
Reaction time: 0.5 h
Yield: 93 %

Procedure:
1-(Methyloxy)-2-propanamine (0.35 g) and 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-nitroquinoline (for a preparation see Intermediate 8) (0.74 g, 2.217 mmol) were dissolved in a mixture of triethylamine (0.30 ml, 2.2 mmol) and NMP (3 ml) and the solution was allowed to stand for 30 min at room temperature, then diluted with water (20 ml) and the resulting suspension stirred for 20 min, then filtered and the resulting solid washed with water (10 ml) and dried in the vacuum oven at 50° C. to give the title compound as bright yellow solid. (0.80 g, 2.070 mmol, 93% yield). LCMS (formate) Rt 0.97 MH+ 387
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([C:34]2[N:39]=[CH:38][C:37]([C:40]([OH:42])=O)=[CH:36][N:35]=2)[CH:31]=[CH:32][CH:33]=1)[CH3:26].CCN(C(C)C)C(C)C.[F:52][C:53]([F:66])([F:65])[C:54]1[NH:55][C:56]2[C:61]([CH:62]=1)=[CH:60][C:59]([CH2:63][NH2:64])=[CH:58][CH:57]=2>CN(C=O)C>[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([C:34]2[N:35]=[CH:36][C:37]([C:40]([NH:64][CH2:63][C:59]3[CH:60]=[C:61]4[C:56](=[CH:57][CH:58]=3)[NH:55][C:54]([C:53]([F:66])([F:52])[F:65])=[CH:62]4)=[O:42])=[CH:38][N:39]=2)[CH:31]=[CH:32][CH:33]=1)[CH3:26]
Reactant: CCOc1cccc(-c2ncc(C(=O)O)cn2)c1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cccc(-c2ncc(C(=O)NCc3ccc4[nH]c(C(F)(F)F)cc4c3)cn2)c1
Reaction time: 24 h
Yield: 45.4 %

Procedure:
To a stirred solution of HATU (30.3 mg, 0.080 mmol) in DMF (1 ml) was added 2-[3-(ethyloxy)phenyl]-5-pyrimidinecarboxylic acid (Intermediate 7, 10 mg, 0.041 mmol) in DMF (0.5 ml), followed by DIPEA (0.021 ml, 0.120 mmol) and finally {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 4, 10 mg, 0.040 mmol) in DMF (1 ml). The solution was stirred for 24 hrs then DMF was removed using a rotary evaporator. DCM and sodium bicarbonate solution were then added to the residue. The mixture was poured through a phase separation cartridge, the organic layer evaporated to dryness and purified using MDAP to give the title compound as a yellow solid (8 mg);
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CON(C)[C:35](=[O:43])[C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[N:38][CH:37]=1>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35]([C:36]3[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=3)=[O:43])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1ccc(C)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccc(C)nc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 33.7 %

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (90 mg, 0.2 mmol) in 2.0 mL of THF under nitrogen atmosphere at −78° C. was added drop-wise 0.3 mL (0.6 mmol) of isopropylmagnesium chloride. The mixture was then stirred for 10 min at −78° C. followed by warming to room temperature and stirred at that temperature for 30 min. The mixture was cooled to 0° C. (ice water) and a solution of N-methoxy-6,N-dimethyl-nicotinamide (72mg, 0.4 mmol) in 1 mL of THF was added. The mixture was stirred at room temperature for 3 hours, quenched with 1M HCl and neutralized with 1M NaOH until pH was 9. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was purified by flash column (silica gel, 50% ethyl acetate in hexane) to afford 36 mg of 4-chloro-N-[5-chloro-2-(6-methyl-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide as an off white solid. MS: (M+H)/z=534.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][CH:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C:7](=[O:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11]
Reactant: COC(=O)[C@@H]1CC(O)CN1C(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A mixture of 12.7 g of N-t-butoxycarbonyl-4-hydroxyproline methyl ester and 44.7 g of pyridinium chlorochromate in 150 ml of methylene chloride is stirred at room temperature for 30 hours, diluted with 200 ml of ether and filtered through Florisil washing with ether (500 ml). The solution is evaporated to dryness, the residue is purified by flash chromatography on silica gel using ethyl acetate/hexane (40:60) as eluent to give N-t-butoxycarbonyl-4-oxoproline methyl ester.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]=[CH2:8])([CH3:4])([CH3:3])[CH3:2].C(OOC(C)(C)C)(C)(C)C.[C:19]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C:19]1=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCCC1
Reactant: C=CCOC(C)(C)C
Agent: CC(C)(C)OOC(C)(C)C
Product: CC(C)(C)OCCCC1CCCCC1=O
Yield: 60 %

Procedure:
A solution of 114 g (1 mole) of allyl tert.-butyl ether and 29.2 g (0.2 mole) of di-tert.-butyl peroxide was added over 2 hours to 980 g (10 moles) of cyclohexanone at 140° C., while stirring, and the mixture was then kept at the same temperature for a further hour. Working up the reaction mixture by distillation gave 2-(3-tert-butoxy-prop-1-yl)-cyclohexanone in 60% yield.
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[CH2:31]([O:33][C:34]1[C:35]([CH:40]=O)=[N:36][CH:37]=[CH:38][CH:39]=1)[CH3:32].[C:42]([BH3-])#[N:43].[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:43]([CH2:42][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)[CH2:40][C:35]3[C:34]([O:33][CH2:31][CH3:32])=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: [BH3-]C#N
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: CCOc1cccnc1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncccc3OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
The compound (104 mg) obtained in Example 47-3 was dissolved in methanol (5.0 ml) and added with 3-ethoxy-2-pyridine aldehyde (74.7 mg) synthesized by the method described in Marsais, F et al, Synthesis, 235 (1982), followed by the addition of sodium cyanoborohydride (46.6 mg). After that, the reaction solution was adjusted to about pH 5 with acetic acid and then stirred at room temperature for 65 hours. The reaction solution was added with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The resulting crude product was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (132 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][C@H:9]1[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1ccccc1Br)C1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1c2ccccc2OC[C@H]1C1CCCCC1
Yield: 67.5 %

Procedure:
A mixture of (R)-2-(2-tert-butoxycarbonylamino-2-cyclohexylethoxy)bromobenzene (500 mg, 1.26 mmol), tetrakis(triphenylphosphine)palladium(0) (146 mg, 0.126 mmol) and sodium tert-butoxide (181 mg 1.88 mmol) in toluene (4.0 ml) was exposed to microwave irradiation for 10 min at 120° C. The resulting mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography eluting with 0-17% (v/v) ethyl acetate in heptane to afford (R)-4-tert-butoxycarbonyl-3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (270 mg, 0.85 mmol). This reaction was repeated 13 times on the same scale to afford the same intermediate (a total of 3.98 g, 12.5 mmol).
Reaction SMILES: [NH:1]1[CH2:5][N:4]([NH2:6])[CH:3]=[N:2]1.[Br:7][CH2:8][C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=[O:10]>C(#N)C>[Br-:7].[NH2:6][N:4]1[CH2:5][NH+:1]([CH2:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])[N:2]=[CH:3]1
Reactant: O=C(CBr)c1cccc2ccccc12
Reactant: NN1C=NNC1
Solvent: CC#N
Product: NN1C=N[NH+](CC(=O)c2cccc3ccccc23)C1
Product: [Br-]
Reaction time: 3 h
Yield: 122 %

Procedure:
A mixture of 1H-1,2,4-triazol-4-amine (44 g), 2-bromo-1-(1-naphthalenyl)ethanone (200 g) and acetonitrile (1000 ml) was stirred for 3 hours at reflux temperature. After cooling, the precipitated product was filtered off, washed with acetonitrile and dried in vacuo, yielding 209 g (78.4%) of 4-amino-1-[2-(1-naphthalenyl)-2-oxoethyl]-1H-1,2,4-triazolium bromide; mp. 170° C. (interm. 7).
Reaction SMILES: [C:1]1([C:7]([CH:9]=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C@H:12]([C:14]([NH2:16])=[O:15])[CH3:13].[OH-].[Na+]>CO>[CH3:13][C:12]1[C:14](=[O:15])[NH:16][CH:9]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: C[C@H](N)C(N)=O
Reactant: O=CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(-c2ccccc2)c[nH]c1=O
Temperature: 41 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
This compound was prepared following the procedure of Jones (J. Amer. Chem. Soc. 1949, 71, 78-81). Briefly, commercially available phenylglyoxal 22 (1.02 g, 7.62 mmol) was dissolved in methanol and cooled to 41° C. Commercially available alanine amide 23 (672 mg, 7.62 mmol) was dissolved in 25 ml methanol and added to the reaction mixture. A 12.5 N NaOH (0.760 mL, 9.53 mmol) solution was added dropwise while stirring, maintaining the temperature of the reaction below 40° C. When the addition was complete, the reaction was placed at =5° C. for 2 h. The reaction was then warmed to room temperature and quenched with 12 N HCl solution (0.76 mL), followed by sodium bicarbonate to neutralize the solution. The methanol was removed under reduced pressure, and the residue was extracted with chloroform and precipitated with ethyl acetate. The compound was isolated as a white powder to give 24 in 18% yield. HPLC (tr/purity): 1531 min, >97%. ESI m/z (MeOH): 187.35 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.Cl.[NH2:18][C:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[C:21]([O:26][CH3:27])[N:20]=1.O.N>P(Cl)(Cl)(Cl)=O>[CH3:15][N:2]([CH3:1])[C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([NH:25][C:24]1[C:19]([NH2:18])=[N:20][C:21]([O:26][CH3:27])=[CH:22][CH:23]=1)=[O:7]
Reactant: CN(C)c1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: COc1ccc(N)c(N)n1
Agent: Cl
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2N(C)C)c(N)n1

Procedure:
An amount of 1.05 gm of 2-dimethylamino-4-nitro-benzoic acid is suspended in 35 ml of phosphorus oxychloride, and 1.05 gm of 2,3-diamino-6-methoxy-pyridine dihydrochloride are added thereto. The mixture is refluxed for 5 minutes, left to cool for 15 minutes with stirring, and finally decomposed with water. The solution obtained is cooled and poured onto a mixture of ice and concentrated ammonia. The product is then precipitated. It is subjected to suction filtration, washed with water, and dried in a circulating air drier at 50° C.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+]>CO.O1CCOCC1.O.[Ni]>[O:6]([C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])[C:5]1[CH:13]=[CH:14][CH:2]=[CH:3][CH:4]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(Oc1ccccc1)C(=O)O
Reaction time: 3.25 h
Yield: 9.5 %

Procedure:
To a solution of 20.0 g (0.93 mole) of 2-(4-chlorophenoxy)-2-methylpropionic acid (97%, clofibric acid, Aldrich) in 130 ml of methanol and 50 ml of dioxane was added a solution of 13.9 g (0.244 mole) of potassium hydroxide in 75 ml of water. To this solution were added 5 teaspoonfuls of Raney Nickel (Aldrich) and the mixture was hydrogenated at ambient temperature for 3.25 hr (H2 -uptake ceased). The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to a volume of 150 ml. This solution was extracted with 200 ml of ethyl ether and the ether was discarded. The aqueous layer pH was adjusted to 2 with concentrated hydrochloric acid solution and the resulting white solid was collected by filtration and dried to give 16 g (99%) of white solid. An analytical sample was prepared by recrystallizing from cyclohexane-petroleum ether (b.p. range 30°-60° C.) to give white crystals, mp 98°-100° C.