Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]([CH2:24][C:25]2[CH:35]=[CH:34][C:28]([C:29](OCC)=[O:30])=[CH:27][CH:26]=2)=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:29][OH:30])=[CH:34][CH:35]=2)=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(CC(=O)NC(c2ccc(C)cc2)c2ccccc2N2CCCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C(NC(=O)Cc2ccc(CO)cc2)c2ccccc2N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Two and one-half grams (5.3 m mol) of ethyl 4-{N-[α-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl}-benzoate were added in batches to a suspension of 0.5 gm (13.2 m mol) of lithium aluminium hydride in 50 ml of absolute tetrahydrofuran. The mixture was stirred for a further 30 minutes at ambient temperature, decomposed by the dropwise addition of 4N sodium hydroxide solution, and filtered to remove the sodium aluminate formed. The filtrate was concentrated by evaporation, and the residue was recrystallized from a small amount of toluene.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].ON1C2C=CC=CC=2N=N1.[CH3:25][S:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)(=[O:28])=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:2]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:33](=[O:34])[C:32]2[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:37][CH:36]=2)[CH2:13][CH2:14]1)([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 22 °C
Reaction time: 23 h
Yield: 90.6 %

Procedure:
To an ice-cooled slurry of 4-N-BOC-amino-piperidine (400.8 mg, 2.0 mmol), 1-hydroxybenzotriazole (HOBt, 342.3 mg, 2.53 mmol), and p-(methylsulfonyl)-benzoic acid (445.9 mg, 2.23 mmol) in dichloromethane (6 mL) is added 1,3-dicyclohexylcarbodiimide (DCC, 496.7 mg, 2.40 mmol). The reaction mixture is stirred at 22° C. for 23 hours. The crude product is purified on a silica gel chromatography with ethyl acetate-hexanes to provide a white solid (692.9 mg, 90.6% yield, ES+(m/z) 383.1 [M+H]).
Reaction SMILES: [F:1][CH2:2][C:3]1([S:6]([NH:9][C:10]([C@@:12]23[CH2:27][C@H:26]2[CH:25]=[CH:24][CH2:23][CH2:22][CH:21]([CH3:28])[CH2:20][C@@H:19]([CH3:29])[C@H:18]([NH:30]C(=O)OC(C)(C)C)[C:17](=[O:38])[N:16]2[CH2:39][C@H:40]([O:42][C:43]4[C:52]5[C:47](=[CH:48][C:49]([O:53][CH3:54])=[CH:50][CH:51]=5)[N:46]=[C:45]([C:55]5[CH:60]=[CH:59][C:58]([O:61][CH:62]([CH3:64])[CH3:63])=[CH:57][CH:56]=5)[CH:44]=4)[CH2:41][C@H:15]2[C:14](=[O:65])[NH:13]3)=[O:11])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[ClH:66]>O1CCOCC1>[ClH:66].[NH2:30][C@@H:18]1[C:17](=[O:38])[N:16]2[CH2:39][C@H:40]([O:42][C:43]3[C:52]4[C:47](=[CH:48][C:49]([O:53][CH3:54])=[CH:50][CH:51]=4)[N:46]=[C:45]([C:55]4[CH:60]=[CH:59][C:58]([O:61][CH:62]([CH3:64])[CH3:63])=[CH:57][CH:56]=4)[CH:44]=3)[CH2:41][C@H:15]2[C:14](=[O:65])[NH:13][C@:12]2([C:10]([NH:9][S:6]([C:3]3([CH2:2][F:1])[CH2:4][CH2:5]3)(=[O:7])=[O:8])=[O:11])[CH2:27][C@H:26]2[CH:25]=[CH:24][CH2:23][CH2:22][C@@H:21]([CH3:28])[CH2:20][C@H:19]1[CH3:29]
Reactant: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(CF)CC6)C[C@H]5C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)cc(-c3ccc(OC(C)C)cc3)nc2c1
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(CF)CC6)C[C@H]5/C=C\CCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)cc(-c3ccc(OC(C)C)cc3)nc2c1
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(CF)CC6)C[C@H]5/C=C\CC[C@@H](C)C[C@@H](C)[C@H](N)C(=O)N4C3)cc(-c3ccc(OC(C)C)cc3)nc2c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(CF)CC6)C[C@H]5C=CCC[C@@H](C)C[C@@H](C)[C@H](N)C(=O)N4C3)cc(-c3ccc(OC(C)C)cc3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (2R,6S,7R,13aS,14aR,16aS,Z)-14a-(1-(fluoromethyl)cyclopropylsulfonylcarbamoyl)-2-(2-(4-isopropoxyphenyl)-7-methoxyquinolin-4-yloxy)-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate (130 mg, 0.14 mmole) was added to a solution of HCl in dioxane (4N, 5 mL) and the solution was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure to get crude compound. The crude compound was washed with diethyl ether to afford (2R,6S,7R,9R,13aS,14aR,16aS,Z)-6-amino-N-(1-(fluoromethyl)cyclopropylsulfonyl)-2-(2-(4-isopropoxyphenyl)-7-methoxyquinolin-4-yloxy)-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide hydrochloride (100 mg, 90%) as off-white solid. MS: MS m/z 821.3 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][CH2:11][C@@H:12]([OH:29])[C@@H:13]([NH:21]C(OC(C)(C)C)=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31].O1CCOCC1>C1COCC1>[ClH:31].[CH2:1]([O:8][C:9](=[O:30])[NH:10][CH2:11][C@@H:12]([OH:29])[C@@H:13]([NH2:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)[C@H](O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A solution of ((2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-carbamic acid benzyl ester (D103) (31.5 g, 76.1 mmol, 1 equiv) in THF (300 ml) was treated with 4N HCl solution in dioxan (40 ml, 160 mmol, 2.1 equiv). The resulting solution was stirred at room temperature for 2 h then concentrated in vacuo. The residue was triturated with Et2O/iso-hexane to give ((2R,3S)-3-amino-2-hydroxy-4-phenyl-butyl)-carbamic acid benzyl ester hydrochloride (D104) (22.1 g, 83%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[N:3]=1.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.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>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[N:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CN1CCN(C(=O)c2ccc(Nc3nc(Cl)ccc3C(N)=O)cc2)CC1
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: [K+]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2ccc(Nc3nc(-c4ccc(F)cc4F)ccc3C(N)=O)cc2)CC1
Temperature: 90 °C
Yield: 35.2 %

Procedure:
A mixture of 6-chloro-2-(4-(4-methylpiperazine-1-carbonyl)phenylamino)nicotinamide (40 mg, 0.107 mmol), 2,4-difluorophenylboronic acid (16.90 mg, 0.107 mmol), K2CO3 (29.6 mg, 0.214 mmol), and Pd(Ph3P)4 (12.36 mg, 10.70 μmol) in THF (2 mL) in a microwave vial was degassed by passing nitrogen through briefly. The vial was sealed and heated to 90° C. overnight. The reaction mixture was diluted with CH2Cl2, washed with satd. NaHCO3, water, and concentrated. The residue was purified by prep-HPLC. The product containing fractions were collected, basified by 1N NaOH, extracted with CH2Cl2, washed with water, concentrated to give 17 mg of 6-(2,4-difluorophenyl)-2-(4-(4-methylpiperazine-1-carbonyl)phenylamino)nicotinamide as a yellow solid. LCMS: (M+H)+=452.08 1H NMR (400 MHz, CDCl3) δ ppm 10.80 (1H, s), 8.08 (1H, td, J=8.79, 6.59 Hz), 7.79-7.83 (1H, m), 7.77 (2H, d, J=8.35 Hz), 7.35 (2H, d, J=8.79 Hz), 7.23-7.27 (1H, m), 6.98-7.06 (1H, m), 6.93 (1H, ddd, J=11.42, 8.79, 2.64 Hz), 3.67 (4H, br. s.), 2.36-2.61 (4H, m), 2.33 (3H, s).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][N:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:14][CH:13]([C:25]([OH:27])=O)[CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:28][C:29]1[CH:30]=[C:31]([C:35](=[N:37]O)[NH2:36])[CH:32]=[CH:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[C:31]([C:35]2[N:37]=[C:25]([CH:13]3[CH2:12][CH:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=4)[CH2:16][N:15]([C:17]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[O:18])[CH2:14]3)[O:27][N:36]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: CS(=O)(=O)c1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(=NO)c1cccc(F)c1
Product: CS(=O)(=O)c1ccc(C2CC(c3nc(-c4cccc(F)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
60 mg (0.151 mmol) of the compound from Example 198A and 35 mg (0.227 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 54 mg (67% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]=1)=O)[CH3:2].[C:21]1([CH:28]=CC=[C:24](O)[CH:23]=1)[OH:22].P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[OH:22][C:21]1[CH:28]=[C:1]2[C:2]([C:6]([C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=4)[CH:9]=3)=[CH:5][C:4](=[O:20])[O:3]2)=[CH:24][CH:23]=1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)CC(=O)c1ccc2cc(OC)ccc2c1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2cc(-c3cc(=O)oc4cc(O)ccc34)ccc2c1
Temperature: 0 °C
Yield: 68.8 %

Procedure:
A stirred solution of ethyl(6-methoxy-2-naphthoyl)acetate (36 g, 0.132 mole), resorcinol (14.6 g, 0.132 mole) and phosphoryl chloride (32 ml) in benzene (200 ml) was refluxed for 3 hours. The reaction mixture was allowed to cool, poured into ice/water and filtered to give the crude product as a red solid. Recrystallisation from ethanol gave 7-hydroxy-4(6-methoxy-2-naphthyl)coumarin (28.9 g, 69%) m.p. 223°-225° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([NH2:29])[CH:20]=[CH:21][C:22]=1[N:23]1[C:27]([CH3:28])=[N:26][CH:25]=[N:24]1>ClCCl>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:29][C:19]2[CH:20]=[CH:21][C:22]([N:23]3[C:27]([CH3:28])=[N:26][CH:25]=[N:24]3)=[C:17]([F:16])[CH:18]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ncnn1-c1ccc(N)cc1F
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Solvent: ClCCl
Product: Cc1cc(Cc2ccccc2)nc(Nc2ccc(-n3ncnc3C)c(F)c2)n1

Procedure:
The title compound was prepared from 4-benzyl-2-chloro-6-methyl-pyrimidine (86 mg, 0.54 mmol) and 3-fluoro-4-(5-methyl-[1,2,4]triazol-1-yl)-phenylamine (75 mg, 0.39 mmol) using in analogous manner the procedure described in example 206c). Column chromatography (15 g silica, dichloromethane+3.5% methanol v/v) afforded the title compound as a light yellow waxy solid (100 mg, 68%). 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.07 (dd, 1H), 7.97 (s, 1H), 7.27 (m, 7H), 6.56 (s, 1H), 4.00 (s, 2H), 2.42 (d, 3H), 2.39 (s, 3H). MS ISP (m/e): 375.2 [(M+H)+].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[N:9]=2)[CH2:4][CH2:3]1.CO[Na]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2nn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Agent: CO[Na]
Solvent: CO
Product: CN1CCN(c2n[nH]c3ccccc23)CC1
Yield: 80.3 %

Procedure:
A stirred mixture of 3-(4-methyl-1-piperazinyl)-1-phenylsulfonyl-1H-indazole (13.5 g, 38 mmol), methanol (150 ml) and 25% CH3ONa in methanol (15.3 ml) was stirred and refluxed for 2.5 hours. The reaction was concentrated to about one-tenth its volume, and water was added to the mixture, resulting in a red solution. The solution was extracted with dichloromethane, the extract washed (H2O), dried (MgSO4), and the solvent was concentrated to afford 6.6 g of a rose-colored solid. Two recrystallizations from toluenehexane afforded 4.3 g (52%) of 3-(4-methyl-1-piperazinyl)-1H-indazole as an off-white solid, m.p.=111-113° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([CH3:11])[CH:3]=1.Cl[C:13]1[C:22]([N:23]([CH3:27])[CH:24]([CH3:26])[CH3:25])=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:28]([O:30][CH3:31])=[O:29])[CH:19]=2)[N:14]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[C:22]([N:23]([CH:24]([CH3:26])[CH3:25])[CH3:27])=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:28]([O:30][CH3:31])=[O:29])[CH:19]=3)[N:14]=2)=[C:4]([CH3:11])[CH:3]=1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: Cc1cc(F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3C)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a solution of (4-fluoro-2-methylphenyl)boronic acid (158 mg, 1.03 mmol) in dioxane (5.0 mL) and water (3 drops) was added methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (100 mg, 0.34 mmol), K3PO4 (215 mg, 1.01 mmol) and Pd(PPh3)4 (20 mg, 0.02 mmol), and the reaction was stirred for 1 hour at 95° C. under an inert atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to provide a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 2-(4-fluoro-2-methylphenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (53.0 mg, 42%).
Reaction SMILES: N[C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl.C([O:25][C:26]([C:28]1[N:32]([CH:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)[N:31]=[N:30][CH:29]=1)=[O:27])C.N1(C2CCCCCCCCCC2)CCCCCCCCCN1>>[CH:15]1([N:7]2[C:8]3[C:3](=[CH:2][C:11]([F:12])=[C:10]([N:35]4[CH2:36][CH2:37][CH:33]([N:32]5[C:28]([C:26]([OH:27])=[O:25])=[CH:29][N:30]=[N:31]5)[CH2:34]4)[C:9]=3[F:14])[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6]2)[CH2:17][CH2:16]1
Reactant: CCOC(=O)c1cnnn1C1CCNC1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Agent: Cl
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(n4nncc4C(=O)O)C3)c(F)cc2c1=O
Temperature: 110 °C

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (100 mg, 0.33 mmol), 3-(5-ethoxycarbonyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride (178 mg, 0.83 mmol) and diazabicycloundecane (127 mg, 0.83 mmol) was heated at 110° C. for 24 hrs. The mixture was concentrated, diluted with water and the separated solid was washed with water and acetonitrile. The solid was dried in air and redissolved in methanol (5 ml) and to it NaOH (20 mg) in water (5 ml) was added. The solution was heated at 90° C. for 6 hrs., cooled and pH lowered using 1N HCl to 4. The separated solid was filtered, recrystallized from methanol/ether, yield 20 mg (13.98%), m.p. 214° C. 1H NMR (TFA) δ: 1.30-1.62 (m, 4H), 2.70-3.0 (m, 2H), 3.74-4.80 (m, 5H), 5.60-5.70 (m, 1H), 8.86 (s, 1H), 9.14 (s, 1H).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH2:22]([OH:36])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[CH:22](=[O:36])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCC/C=C\CCCCCCCO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCC/C=C\CCCCCCC=O

Procedure:
15.8 g pyridinium dichromate in 300 ml dichloromethane were initially introduced under blanketing gas and 5.93 g (Z)-8-tetradecen-1-ol (5) in 50 ml dichloromethane was added, with stirring. The reaction mixture was stirred for 15 h at room temperature and filtered through silica gel. Distillation under a high vacuum gave (Z)-8-tetradecenal (6).
Reaction SMILES: C(O)(=O)C=[O:3].CON=[CH:9][C@H:10]([F:31])[C@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:12]([Br:22])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OCC)(=O)C.O>O1CCCC1>[Br:22][C@@H:12]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:10]([F:31])[CH:9]=[O:3]
Reactant: O=CC(=O)O
Reactant: CON=C[C@H](F)[C@H](OCc1ccccc1)[C@@H](Br)COCc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C[C@@H](F)[C@H](OCc1ccccc1)[C@@H](Br)COCc1ccccc1
Temperature: 70 °C
Reaction time: 4.83 h

Procedure:
3.3 mL of a 50% glyoxylic acid aqueous solution was added to a solution of 662 mg of the (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis(benzyloxy)pentanal O-methyloxime in 6.6 mL of tetrahydrofuran, and the obtained mixture was then stirred at 70° C. for 4.83 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 655 mg of colorless oily (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis(benzyloxy)pentanal and a water adduct thereof.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4](N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)[CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(C(F)(F)F)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:34][C:32]([F:33])([F:35])[C:28]1[N:27]=[C:26]([NH:25][C:2]2[CH:3]=[CH:4][N:5]=[CH:6][C:7]=2[C:8]#[N:9])[CH:31]=[CH:30][CH:29]=1
Reactant: Nc1cccc(C(F)(F)F)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Cl)c(C#N)cn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnccc1Nc1cccc(C(F)(F)F)n1
Temperature: 80 °C

Procedure:
A mixture of tert-butyl {(1S,2R)-2-[(4-chloro-5-cyanopyridin-2-yl)amino]cyclohexyl}carbamate (PrepEx 1.1) (80 mg, 0.23 mmol), 2-amino-6-(trifluoromethyl)pyridine (37 mg, 0.23 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (16 mg, 0.034 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), and cesium carbonate (149 mg, 0.456 mmol) in a flask was evacuated and backfilled with nitrogen (3×). Dioxane (1.5 mL) was added, and the reaction mixture was heated to 80° C. for 3 hours. The mixture was allowed to cool to room temperature. TFA (0.386 mL, 5.02 mmol) was added, and the suspension was heated to 65° C. for 14 hours. The mixture was allowed to cool to room temperature, filtered, and concentrated under reduced pressure. The residue was dissolved in DMSO, filtered, and purified via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 6-[(1R,2S)-2-aminocyclohexyl]amino}-4-{[6-(trifluoromethyl)pyridin-2-yl]amino}pyridine-3-carbonitrile. MS ESI calc'd. for C18H20F3N6 [M+H]+ 377. found 377.
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[C:9]1[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]1=[O:18])[CH2:7][CH3:8])[CH:2]=[CH2:3].[OH-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O.O>[CH2:1]([O:4][N:5]=[C:6]([C:9]1[C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][C:14]=1[O:15][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCONC(CC)=C1C(=O)CC(C)(C)CC1=O
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C=CCON=C(CC)C1=C(OCc2ccccc2)CC(C)(C)CC1=O
Temperature: 60 °C
Reaction time: 10 h

Procedure:
To a solution of 2-(1-allyloxyaminopropylidene)-5,5-dimethylcyclohexane-1,3-dione (2.5 g) in acetone (30 ml), sodium hydroxide (0.4 g) in water (2 ml) was added at room temperature and then benzyl bromide (2.0 g) was added. After stirring for 10 hours at 60° C the reaction mixture was poured into ice-water and extracted with chloroform. The extract was washed with one normal sodium hydroxide and dried over magnesium sulfate. The solvent was removed in vacuo and an oily substance which solidified on standing at 0° C was obtained. Recrystallization from the mixture of methanol and water gave the desired product as crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH:20](=O)[CH2:21][CH2:22][CH2:23][CH3:24].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.C(OCC)(=O)C>[O:11]=[C:6]1[C:7]2[C:3](=[C:2]([NH:1][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:10]=[CH:9][CH:8]=2)[CH2:4][N:5]1[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: CCCCC=O
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCNc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 21.3 %

Procedure:
To a stirred solution of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.52 g, 2.0 mmol) in DMF (10 ml) was added pentanal (0.26 g, 3.0 mmol), acetic acid (0.24 g, 4.0 mmol), and sodium triactoxyborohydride (0.85 g, 4.0 mmol). The reaction mixture was stirred at room temperature for 6 hours. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (100 ml), washed with H2O (3×100 ml), brine (1×100 ml), and dried over MgSO4. The solvent was evaporated and the residue was partially purified by chromatography (ethyl acetate/hexane, 75:25) to give an off-white solid which was slurried in ethyl acetate and filtered to give 0.14 g (21%) of product as a white solid: mp 244–246° C.; 1H NMR (DMSO-d6) δ 11.00 (s, 1H), 7.28 (t, J=7.7 Hz, 1H), 6.92 (d, J=7.3 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 5.54 (t, J=5.3 Hz, 1H), 5.12 (dd, J=5.1 and 13.2 Hz, 1H), 4.24 (d, J=17.2 Hz, 1H), 4.13 (d, J=17.2 Hz, 1H) 3.15–3.07 (m, 2H), 3.00–2.86 (m, 1H), 2.65–2.59 (m, 1H), 2.39–2.23 (m, 1H), 2.08–1.99 (m, 1H), 1.61–1.57 (m, 2H), 1.41–1.32 (m, 4H), 0.89 (t, J=6.8 Hz, 3H); 13C NMR (DMSO-d6) δ 172.83, 171.19, 168.86, 143.74, 132.00, 129.15, 126.42, 111.66, 109.86, 51.46, 45.69, 42.68, 31.20, 28.80, 28.21, 22.79, 21.96, 13.89; Anal. Calcd. For C18H23N3O3: C, 65.63; H, 7.04; N, 12.76. Found: C, 65.69; H, 7.22; N, 12.55.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Cl[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.C(OCC)(=O)C>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[N:16]2)[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCn1nnc2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cn1nnc2ccccc21

Procedure:
A solution of potassium phthalimide (5.55 g) and crude 1-(chloromethyl)benzotriazole (5.02 g) in 75 ml dimethylformamide was stirred at ambient temperature for 2 hours. An additional portion of potassium phthalimide (1.0 g) was added. After 2 hours an aqueous ethyl acetate extractive work up gave a crude solid. Recrystallization from acetonitrile gave a colorless solid, m.p. 177°-180° C. (5.49 g).