Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:19])[C@H:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[NH2:13].[CH:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])=[O:21]>O1CCCC1>[CH3:9][O:10][C:11](=[O:19])[CH:12]([NH:13][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([CH:20]=[O:21])[CH:23]=1)[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: O=Cc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CC(NC(=O)c1cccc(C=O)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.4 %

Procedure:
A mixture of 30 ml of tetrahydrofuran, 12 ml of triethylamine and 4.11 g of aspartic acid dimethyl ester hydrochloride was added dropwise to a solution of 3.50 g of 3-formylbenzoic acid chloride in 30 ml of tetrahydrofuran at 10° C. After stirred at room temperature for 6 hours, insolubles were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 3.01 g of oily 2-[3-formyl-(benzoylamino)]succinic acid dimethyl ester [Compound No. (p)].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=O)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:27][C:28]([NH:30][NH2:31])=[O:29].O>C1COCC1>[CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]([NH:31][NH:30][C:28](=[O:29])[CH3:27])=[O:14])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)NN
Reactant: COc1cccc2oc(C(=O)O)cc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2oc(C(=O)NNC(C)=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a solution (700 ml) of 4-methoxybenzo(b)furan-2-carboxylic acid (43.4 g) in THF was added 1,1′-carbonylbis-1H-imidazole (CDI) (38.4 g) and the mixture was stirred at room temperature for 1 hr. Acetohydrazine (17.6 g) was added to this reaction mixture, and the mixture was stirred for 1 more hr. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration and dried to give the title compound (38.4 g) as pale-brown crystals.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]([C:47]([O:49]C(C)(C)C)=[O:48])[CH2:43][CH2:44][S:45][CH3:46].Cl>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:41][C@H:42]([C:47]([OH:49])=[O:48])[CH2:43][CH2:44][S:45][CH3:46])=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSCC[C@H](N)C(=O)OC(C)(C)C
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Agent: Cl
Product: CSCC[C@H](NC(=O)CCCc1ccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)cc1)C(=O)O

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and H-Met-OtBu HCl (48 mg, 0.2 mmole) were processed as in Example 213A-B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ11.65-13.33 (br.s, 1 H), 8.95 (s, 1 H), 8.07 (d, 1 H), 7.26 (m, 6 H), 7.19 (m, 3 H), 7.04 (m, 1 H), 6.97 (m, 2 H), 6.89 (m, 4 H), 4.30 (m, 1 H), 4.05 (s, 2 H), 4.02 (s, 2 H), 2.91 (s, 3 H), 2.55 (m, 2 H), 2.46 (m, 2 H), 2.39 (s, 3 H), 2.14 (m, 2 H), 2.03 (s, 3 H), 1.95 (m, 1 H), 1.80 (m, 3 H); MS (APCI+) m/z 646 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH:35][CH2:36][CH2:37][O:38][CH3:39])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH:35][CH2:36][CH2:37][O:38][CH3:39])(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: COCCNS(=O)(=O)c1cccc(Br)c1
Product: COCCNS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 3-bromo-N-(2-methoxy-ethyl)-benzenesulfonamide (example B.33) (265 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (320 mg, 57%). MS (ISP) 551.3 [(M+H)+]; mp 147-148° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCC1=O
Reaction time: 1 h
Yield: 70 %

Procedure:
The nitrogen purged vessel containing about 4-oxo-1,3-piperidinedicarboxylic acid 1-(1,1-dimethylethyl) 3-methyl ester (prepared according to Preparation Five, Step C, 53 kg, 49 L, 1.0 eq.) was charged with tetrahydrofuran (THF, 536 L) and potassium carbonate (72 kg, 2.5 eq.). The slurry was treated with benzyl bromide (36.0 kg, 1.01 eq.) over 10 to 15 minutes. The reaction mixture was heated at reflux temperature until reaction was complete (generally between 12 and 18 hours). The mixture was cooled to between 20° C. and 25° C., filtered to remove the salts, and the filter cake washed with THF (134 L). The THF was removed from the mixture by partial vacuum distillation and replaced with heptanes (402 L). The resulting slurry was cooled to between −5° C. and 5° C. and stirred for about one hour. The solids were collected by filtration, washed with heptanes (57 L) cooled between 0° C. to 10° C., and dried under vacuum between 45° C. to 55° C. to give 50.1 kg of 4-oxo-3-(phenylmethyl)-1,3-piperidinedicarboxylic acid 1-(1,1-dimethylethyl) 3-methyl ester (69.2% yield). HPLC assay showed a product peak of 99.2% at about 12 minutes. HPLC conditions: Intersil C-8 column, 4.6×150 mm; mobile phase: 50% acetonitrile/water; aqueous phase: 1 L water, 3 mL triethylamine and 1 mL H3PO4 at pH 6.5; flow rate 1.0 mL/min.; detected by UV at 210 nm.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][NH:26][CH2:27][C:28]([OH:31])([CH3:30])[CH3:29])[C:5]1=[O:34])[CH:2]=[CH2:3].[C:36](N1C=CN=C1)(N1C=CN=C1)=[O:37]>O1CCOCC1>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]2[CH2:27][C:28]([CH3:29])([CH3:30])[O:31][C:36]2=[O:37])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNCC(C)(C)O)C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CC(C)(C)OC2=O)C1=O

Procedure:
To a solution of 42 mg (0.081 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-hydroxy-2-methylpropylamino)butan-2-yl)-3-methylpiperidin-2-one (Example 100, Step A) in dioxane (2705 μL) was added carbonyldiimidazole (132 mg, 0.812 mmol). The reaction was heated to 100° for 6 h. Purification of the residue by reversed phase HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.) (eluent: 60 to 85% MeCN/water (0.1% TFA), gradient elution) provided the title compound.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[CH2:7][CH2:6]1)=[N+]=[N-].Cl.[H][H]>[Pd].C(O)C.O>[NH2:1][CH2:4][C@@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: CCCCOC(=O)[C@H]1CC[C@@H](CN=[N+]=[N-])CC1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCOC(=O)[C@H]1CC[C@@H](CN)CC1

Procedure:
A mixture of butyl cis-4-(azidomethyl)cyclohexanecarboxylate (27.85 g, 116 mmol), 6N hydrochloric acid (39 ml, 234 mmol) and 10% palladium on carbon (3.78 g) in ethanol (500 ml) was hydrogenated (hydrogen balloon) for 2.5 days. The catalyst was removed by filtration through Celite. The filter cake was washed with ethanol (3×50 ml) and the filtrate was concentrated under reduced pressure to give a gum. The gum was taken up in water (250 ml) and washed with ether (250 ml). The aqueous layer was basified to pH 10 with 10N sodium hydroxide solution and extracted with ethyl acetate (3×250 ml). The ethyl acetate layer was washed with water (100 ml) and brine (100 ml), dried (sodium sulfate), filtered, and the solvent was evaporated under reduced pressure to give butyl cis-4-(aminomethyl)cyclohexanecarboxylate (15.25 g, 62%) as a gum: 1H NMR (CDCl3) 4.08 (2H, t, J 7 Hz), 2.57 (2H, d, J 8 Hz), 2.02 (2H, m), 1.66-1.51 (6H, m), 1.45-1.23 (5H, m), 0.94 (3H, t, J 7 Hz). MS: 214.2 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[C-:9]#[N:10].[Na+]>CS(C)=O.C(OCC)(=O)C>[C:9]([C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1)#[N:10]
Reactant: [C-]#N
Reactant: Fc1cc(I)ccn1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(I)ccn1
Temperature: 100 °C
Yield: 5 %

Procedure:
2-Fluoro-4-iodopyridine (4.99 g, 22.4 mmol) prepared according to a known method (WO2005/041663) was dissolved in dimethyl sulfoxide (75 mL), and the mixture was stirred at 100° C. after adding sodium cyanide (1.21 g, 24.7 mmol). The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with an aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was purified by silica gel column chromatography to give 2-cyano-4-iodopyridine (258 mg, 5%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:59][C:60]1[CH:61]=[C:62]2[C:67](=[CH:68][CH:69]=1)[CH:66]=[C:65]([N:70]1[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1)[CH:64]=[CH:63]2>ClCCl>[F:59][C:60]1[CH:61]=[C:62]2[C:67](=[CH:68][CH:69]=1)[CH:66]=[C:65]([N:70]1[CH2:71][CH2:72][N:73]([C:19](=[O:21])[CH2:18][O:17][CH:14]3[CH2:15][CH2:16][CH:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:24])([F:23])[F:25])[CH:6]=4)[CH2:12][CH2:13]3)[CH2:74][CH2:75]1)[CH:64]=[CH:63]2
Reactant: Fc1ccc2cc(N3CCNCC3)ccc2c1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
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: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc3cc(F)ccc3c2)CC1
Reaction time: 8 h
Yield: 11.3 %

Procedure:
To a solution of 2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)-oxy]acetic acid (173 mg, 0.48 mmol, 1 eq) in dichloromethane (50 ml) was added DIEA (61.8 mg, 0.48 mmol, 1 eq), HATU (182 mg, 0.48 mmol, 1 eq) and 1-(6-fluoronaphthalen-2-yl)piperazine (110 mg, 0.48 mmol, 1 eq) at room temperature under an inert atmosphere of nitrogen. The resulting solution was stirred overnight. The reaction was then quenched by the addition of water (100 ml) and extracted with dichloromethane (3×50 ml) and the organic layers were combined and then dried over anhydrous sodium sulfate. The solids were filtered off. The resulting mixture was concentrated under vacuum to give a residue, which was applied onto a silica gel column and eluted with 2% methanol in dichloromethane. The product-containing fractions were combined and concentrated under vacuum to afford 1-[4-(6-fluoronaphthalen-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (31.1 mg, 11%); (ES, m/z): [M−H]− 573.2; 1H NMR (300 MHz, DMSO/D2O): δ 8.05 (d, J=6.9 Hz, 1H), 7.77-7.82 (m, 2H), 7.53-7.56 (dd, J=1.8, 7.5 Hz, 1H), 7.43-7.46 (dd, J=1.5, 6.9 Hz, 1H), 7.28-7.33 (m, 1H), 7.25 (d, J=1.2 Hz, 1H), 7.06 (s, 1H), 6.83-6.86 (dd, J=1.8, 6.9 Hz, 1H), 4.21 (s, 2H), 3.63 (broad s, 4H), 3.37-3.52 (m, 2H), 3.21-3.26 (m, 4H), 1.94-2.05 (m, 4H), 1.34-1.39 (m, 2H), 1.23-1.29 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](O[Si](C)(C)C)=[C:5](O[Si](C)(C)C)[CH2:4]1)[CH3:2].[ClH:19].Cl.[NH2:21][CH2:22][C:23]([NH2:25])=[NH:24]>>[ClH:19].[ClH:19].[NH2:25][C:23]1[N:24]=[C:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]2=[N:21][CH:22]=1
Reactant: CCN1CCC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Reactant: N=C(N)CN
Agent: Cl
Product: CCN1CCc2nc(N)cnc2C1

Procedure:
This compound was prepared analogous to Example 22 from 1-ethyl-1,2,5,6-tetrahydro-3,4-bis(trimethylsilyloxy)-pyridine and α-amino-acetamidine dihydrochloride.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([OH:37])=[C:13]2[C:18](=[CH:19][N:20]=1)[N:17](CC1C=CC=CC=1)[C:16](=[O:28])[C:15]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=[CH:14]2)=[O:10])C.[OH-].[Na+].CO>C1COCC1>[CH2:15]([N:20]1[CH:19]=[C:18]2[C:13](=[CH:14][CH:15]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:16](=[O:28])[NH:17]2)[C:12]([OH:37])=[C:11]1[C:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:38])=[O:10])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)CCCNC(=O)c1ncc2c(cc(-c3cccc(OC)c3)c(=O)n2Cc2ccccc2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(C2C=C3C(=CN(Cc4ccccc4)C(C(=O)NCCCC(=O)O)=C3O)NC2=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 132.5 %

Procedure:
A mixture of 4-{[1-benzyl-5-hydroxy-3-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carbonyl]-amino}-butyric acid ethyl ester (38 mg, 0.074 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washes several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 24 mg of the title compound as a yellow solid. MS: (+) m/z 488.40 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:23]([F:27])([F:26])[CH:24]=[CH2:25].O>CN(C)C=O>[F:26][C:23]([F:27])=[CH:24][CH2:25][O:14][C:13]([CH:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: C=CC(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCC=C(F)F)C1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of pyrrolidine-1,3-dicarboxylic acid-1-tert-butyl ester (3.40 g) in N,N-dimethylformamide (34 ml) were added potassium carbonate (4.37 g) and 3-bromo-3,3-difluoropropene (1.93 ml), and the mixture was stirred at 60° C. for 6 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to give the titled compound (3.73 g).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7](=[O:10])[CH2:8][Br:9])[O:4][N:3]=1.B.C1COCC1>>[Br:9][CH2:8][C@@H:7]([C:5]1[O:4][N:3]=[C:2]([Br:1])[CH:6]=1)[OH:10]
Reactant: O=C(CBr)c1cc(Br)no1
Agent: B
Solvent: C1CCOC1
Product: O[C@@H](CBr)c1cc(Br)no1

Procedure:
The title compound was prepared from 3-bromo-5-(bromoacetyl)isoxazole (which was obtained in Example 118), (R)-2-methyl-CBS-oxaborolidine monohydrate, and 1M BH3/THF solution in substantially the same manner, as described in Example 103 with one change; the crude product was purified by flash chromatography and reverse phase chromatography to give a colorless oil (1.45 g, 16% yield): 1H NMR (300 MHz, CDCl3) δ 3.67 - 3.81 (m, 2H), 5.16. (m, 1H), 6.49 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:18](=[O:20])[CH3:19])=[C:5]([CH3:10])[CH:4]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(C)=O)c(C)c1
Reaction time: 1.33 h
Yield: 90.4 %

Procedure:
4-Methoxy-2-methylaniline (26.06 g, 190 mmol) and triethylamine (43 ml, 309 mmol) were dissolved in dichloromethane, acetic anhydride (25 ml, 265 mmol) was added under ice-cooling, and the mixture was stirred at the same temperature for 80 min. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained solid was filtered, washed with hexane, and dried under reduced pressure to give the title compound (30.78 g, yield 90%) as a pale-pink solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:15].OS(O)(=O)=O.O=[Cr](=O)=O.C(OCC)(=O)C>CC(C)=O>[CH2:1]([O:8][CH2:9][CH2:10][C:11]([OH:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: OCCCOCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: O=C(O)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 3-benzyloxy-1-propanol (1.66 g) dissolved in acetone (10 ml) was added 2N Jones reagent (10 ml) while cooling on ice, and the mixture was stirred for 4 hours at room temperature. Ethyl acetate was added, and the resultant mixture was washed with water. The organic layer was extracted with a sat. aq. K2CO3, and the aqueous layer was washed with ethyl acetate. The washed material was acidified with dilute HCl, again extracted with ethyl acetate, then washed with saturated brine. Drying over anhydrous magnesium sulfate and concentrating under reduced pressure yielded 1.27 g of 3-benzyloxypropionic acid as a colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]([C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].Br[C:20]1[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=1.O>COCCOC.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>[CH3:8][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([C:20]2[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:12][CH:11]=1)[CH3:9]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: Nc1ncccc1Br
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: COCCOC
Solvent: O
Product: CC(C)c1ccc(-c2cccnc2N)cc1
Yield: 92.4 %

Procedure:
A mixture of 2M aqueous sodium carbonate solution (8.67 mL), tetrakis(triphenylphosphine)palladium(0) (668 mg), 4-isopropylphenylboronic acid (2844 mg) and 3-bromopyridin-2-amine (2.0 g) in 1,2-dimethoxyethane (30 mL) was heated under reflux overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2267 mg) as a white solid.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[C:15]1([S:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][S:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1ccncc1
Reactant: NCCSc1ccccc1
Solvent: CO
Product: N#CNC(=NCCSc1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 ml), and 2-phenylthioethylamine (0.49 g, 3.2 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 10 g) eluting with chloroform-methanol (50:1). The eluted fractions were concentrated under reduced pressure and crystallized from diethyl ether to give the title compound (0.49 g, 1.7
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[C@@H:11]1([NH:21][CH2:1][C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: N#Cc1cccc(C=O)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: N#Cc1cccc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3-Formylbenzonitrile and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](OCC)=[O:14])[CH:10]=[N:9]2)=[C:5]([CH3:18])[O:4][N:3]=1.[NH2:19][NH2:20]>CCO>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([NH:19][NH2:20])=[O:14])[CH:10]=[N:9]2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: CCOC(=O)c1cnn(Cc2c(C)noc2C)c1
Reactant: NN
Solvent: CCO
Product: Cc1noc(C)c1Cn1cc(C(=O)NN)cn1
Yield: 97.4 %

Procedure:
Ethyl 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carboxylate (example 10-1c) (6 g, 24 mmol) and hydrazine (7.5 g, 240 mmol) were stirred in EtOH (100 mL) at reflux for 12 hours. The solution was concentrated on the rotovap and the solid product was triturated with ethyl acetate/hexanes (1/9) and dried under high vacuum to afford 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carbohydrazide (5.5 g, 97%) as a pure white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.39 (s, 3H), 5.15 (s, 2H), 7.81 (s, 1H), 8.17 (s, 1H), 9.31 (bs, 1H).