Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[CH2:14][O:15][C:16]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>N1C=CC=CC=1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:45]([C:42]2[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=2)(=[O:47])=[O:46])[CH2:10][C@@H:9]1[CH2:14][O:15][C:16]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(OC[C@H]2C[C@@H](O)CN2C(=O)OC(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OC(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
(2R,4R)-1-(tert-Butyloxycarbonyl)-2-(4,4'-Dimethoxytrityl) oxymethyl-4-hydroxypyrrolidine 38 (8.09 g, 20.27 mmol) was dissolved in dry pyridine/CH2Cl2 (2:1, 200 ml) and chilled in an ice bath under argon atmosphere. To this cold solution was added TEA (3.03 g, 30 mmol) followed by p-toluenesulphonyl chloride (5.7 g, 30 mmol). The reaction mixture was allowed to stir at 0° C. for 3 h and below 30° C. for 8 h. The reaction mixture was evaporated to dryness, partitioned between EtOAc (200 ml) and 5% NaHCO3 solution (100 ml), and extracted in EtOAc. The EtOAc extract was washed with water (100 ml) and brine (100 ml), dried and evaporated to dryness. The crude product was purified by flash chromatography over silica gel using hexane→EtOAc as the eluent. The pure fractions were pooled together and evaporated to give 12.2 g (89%) of an orange oil. 1HNMR (CDCl3): 1.45 (s, 9H, Boc), 1.90 (dd, 1H), 2.34 (m, 1H), 2.40 (s, 3H, CH3), 3.40-3.62 (m, 3H), 3.74 (s, 6H, 2.OCH3), 4.00 (m, 2H), 4.28 (bs, 1H), 4.44 (m, 1H), 6.82 (d, 4H, Ph), and 7.26-8.00 (m, 13H, Ph).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH:10](=O)[CH:11]=O>C(O)(=O)C.C([O-])(=O)C.[Na+].O>[N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([OH:9])[C:2]=2[N:1]=[CH:11][CH:10]=1
Reactant: Nc1cccc(O)c1N
Reactant: O=CC=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Oc1cccc2nccnc12
Temperature: 60 °C

Procedure:
2,3-Diaminophenol (2 g) in 10 ml acetic acid and 20 ml 4M sodium acetate and a solution of oxalaldehyde (4.8 g) dissolved in 20 ml water were combined and the resulting mixture was heated at 60° C. for 1.5 h. After cooling to RT water (100 ml) was added and the mixture extracted with EtOAc. The organic layer was dried over Na2SO4, and concentrated to give quinoxalin-5-ol. MS (ESI+) for m/z 147 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]I.[OH-].[Na+].Cl>CC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.7 %

Procedure:
This preparation is similar to that reported by Krapcho et. al. for Cbz-Mop-OH. (Krapcho et. al. J. Med. Chem. 31:1148-1160 (1988)). To a solution of N-tert-Butoxycarbonyl-(2S,4R)-4-hydroxyproline (Boc-Hyp-OH, 2.00 g, 8.65 mmol) and CH3I (1.90 mL, 30.3 mmol) in acetone (50 mL) was added Ag2O (6.50 g, 28.1 mmol). The vessel was purged with Ar(g) and sealed with a septum, and the resulting suspension was stirred at room temperature for 24 h. The mixture was filtered and evaporated to a residue under reduced pressure. The residue was dried under high vacuum for 1 h, and then resubmitted to the reaction conditions a second time. After filtering and evaporating, the residue was dissolved in H2O (60 mL), a solution of NaOH (0.36 g, 9.08 mmol) in 1 mL H2O was added, and the solution was stirred at room temperature for 24 h (to hydrolyze any methyl ester that might have formed during alkylation). The aqueous mixture was acidified to pH 1 by the addition of 3 N HCl(aq) and extracted with CH2Cl2 (3×60 mL). The combined organic layers were dried over MgSO4(s) and evaporated under reduced pressure, and the product was then isolated by flash chromatography (100:0-95:5 CH2Cl2/MeOH) affording Boc-Mop-OH (0.97 g, 46%) as a tinted residue. 1H NMR (500 MHz, CDCl3, ˜3:2 ratio of 2 rotamers): δ 4.44 (t, J=7.5 Hz, 0.6 H), 4.34 (t, J=7.9 Hz, 0.4 H), 4.01-3.95 (m, 1 H), 3.70-3.65 (m, 0.4 H), 3.60-3.52 (m, 1 H), 3.49 (dd, J=11.7, 4.8 Hz, 0.6 H), 3.33 (overlapping s, 3 H), 2.46-2.36 (m, 1 H), 2.32-2.24 (m, 0.6 H), 2.17-2.07 (m, 0.4 H), 1.49 (s, 5.4 H), 1.43 (s, 3.6 H);
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([OH:17])[CH2:14]2)[N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:9])#[N:2].F[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([O:17][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:14]2)[N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)N1CCC[C@H]1C#N
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2Oc2ccccn2)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 63 %

Procedure:
To a solution of tert-butyl (1R,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 5-7 (209 mg) in dimethylformamide (2.5ml), were added 2-fluoropyridine (109 mg) and sodium hydride (60% in mineral oil, 25 mg). The mixture was then stirred at room temperature for 50 minutes. The reaction mixture was diluted with ethyl acetate, and washed successively with water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate to give the target compound (162 mg).
Reaction SMILES: [CH2:1]([N:5]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[C:7]([C:13]([NH:15][C:16]2[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:24][CH3:25])=[O:14])=[C:6]1[CH3:26])[CH2:2][CH2:3][CH3:4].[Br:27]N1C(=O)CCC1=O>ClCCl>[Br:27][C:9]1[C:8](=[O:12])[C:7]([C:13]([NH:15][C:16]2[C:17]([CH2:24][CH3:25])=[CH:18][CH:19]=[CH:20][C:21]=2[CH2:22][CH3:23])=[O:14])=[C:6]([CH3:26])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:10]=1[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCn1c(C)cc(=O)c(C(=O)Nc2c(CC)cccc2CC)c1C
Solvent: ClCCl
Product: CCCCn1c(C)c(Br)c(=O)c(C(=O)Nc2c(CC)cccc2CC)c1C
Temperature: 25 °C
Yield: 61.1 %

Procedure:
A mixture of 3.0 g (8.5 mmol, m.p. 110°-112° C.) of 1-butyl-N-(2,6-diethylphenyl)-1,4-dihydro-2,6-dimethyl-4-oxo-3-pyridinecarboxamide and 1.7 g (9.6 mmol) of N-bromosuccinimide was dissolved in 100 ml of dichloromethane, and the mixture was stirred for a day at room temperature. The reaction mixture, transferred to a separatory funnel, was washed with water, saturated sodium bicarbonate and water. The organic layer was dried and concentrated in a known manner to give a crystalline residue, and the residue was recrystallized from a mixture of ethyl acetate and hexane, affording 2.25 g of the title compound having m.p. 158°-160.5° C.
Reaction SMILES: [N:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4](=[O:16])[NH:3][CH:2]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:16][C:4]2[C:5]3[CH2:11][CH2:10][CH2:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[C:6]=3[N:1]=[CH:2][N:3]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1[nH]cnc2c1CCCc1ccccc1-2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2ncnc3c2CCCc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from Example 118B (154 mg, 0.72 mmol), p-toluenesulfonyl chloride (278 mg, 1.44 mmol), DMAP (17 mg, 0.14 mmol) in CH2Cl2 (20 mL) was treated with triethylamine (0.25 mL, 1.8 mmol) and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel eluting with 40% EtOAc/hexanes to provide the title compound. 1H NMR (CDCl3) δ 2.18-2.40 (m, 4H), 2.48 (d, 3H), 2.51-2.58 (m, 2H), 7.25-7.29 (m, 1H), 7.35-7.45 (m, 4H), 7.66-7.73 (m, J=17.63 Hz, 1H), 8.07 (dd, J=15.60, 8.48 Hz, 2H), 8.85 (d, J=8.48 Hz, 1H). MS (M+H)+ m/z 367
Reaction SMILES: S(OCCCCC#C)([C:4]1[CH:10]=[CH:9][C:7](C)=[CH:6][CH:5]=1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+].CO>O>[N:18]([CH2:10][CH2:9][CH2:7][CH2:6][C:5]#[CH:4])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: C#CCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C#CCCCCN=[N+]=[N-]

Procedure:
A mixture containing 0.397 mole of hex-5-yn-1-ol tosylate; 0.76 mole of sodium azide; and one liter of methanol and 200 ml. of water is stirred at 60° C for 4 hours. The mixture is then evaporated under vacuum to remove the majority of the methanol and the remaining concentrate then poured into 500 ml. of ethyl ether, and then extracted three times with water, and dried over anhydrous magnesium sulfate and filtered. The filtrate is then evaporated, under vacuum, affording 1-azidohex-5-yne as a residue.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-:15].[Na+]>>[NH2:6][C:7]1([C:13]([NH2:14])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: [OH-]
Reactant: N#CC1(N)CCCCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C1(N)CCCCC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To 20 g concentrated sulfuric acid at 5° C is added with stirring 10 g of 1-aminocyclohexanecarbonitrile. After the addition, the mixture is heated with stirring at 100° C for 1 hour. The hot solution is then poured onto ice, the solution made strongly basic with 50% aqueous sodium hydroxide solution, and extracted three times with chloroform. The extract is washed with water, saturated NaHCO3 solution, dried, and the solvent removed in vacuo to leave the product, 1-aminocyclohexanecarboxamide, as a crystalline residue, melting point 99°-102° . This can be recrystallized from either benzene or ether or give a pure product, melting point 101°-102° C.
Reaction SMILES: [CH3:1][C:2](=[CH2:49])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:48])[C:19]1[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][O:32][C:33]2[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([O:43][CH3:44])=[O:42])=[CH:35][C:34]=2[O:45][CH3:46])[CH:22]=[CH:21][C:20]=1[OH:47])=[O:4].[CH2:50]([C:55]1[CH:63]=[CH:62][C:58]([C:59](O)=[O:60])=[CH:57][CH:56]=1)[CH2:51][CH2:52][CH2:53][CH3:54].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:49][C:2](=[CH2:1])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:48])[C:19]1[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][O:32][C:33]2[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([O:43][CH3:44])=[O:42])=[CH:35][C:34]=2[O:45][CH3:46])[CH:22]=[CH:21][C:20]=1[O:47][C:59](=[O:60])[C:58]1[CH:62]=[CH:63][C:55]([CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:56][CH:57]=1)=[O:4]
Reactant: CCCCCc1ccc(C(=O)O)cc1
Reactant: C=C(C)C(=O)OCCCCCCCCCCCOC(=O)c1cc(CCCCCCOOc2ccc(/C=C/C(=O)OC)cc2OC)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCCCCCCOC(=O)c1cc(CCCCCCOOc2ccc(/C=C/C(=O)OC)cc2OC)ccc1OC(=O)c1ccc(CCCCC)cc1
Yield: 78.2 %

Procedure:
1.43 g (2.09 mmol) (E)-2-hydroxy-5-[6-[2-methoxy-4-(methoxycarbonylvinyl)phenoxy]oxyhexyl]benzoic acid 11-(2-methylacryloyloxy)undecyl ester, 0.42 g (2.20 mmol) 4-pentylbenzoic acid and 64 mg (0.52 mmol) 4-dimethylaminopyridine were dissolved in 30 ml of dichloromethane. A suspension of 0.42 g (2.20 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 3 ml dichloromethane were added dropwise in the course of 15 minutes. After 20 hour at room temperature the reaction mixture was partitioned between dichloromethane and water; the organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 150 g silica gel using cyclohexane:ethyl acetate 4:1 and subsequent crystallisation form 20 ml isopropyl alcohol yielded 1.40 g (78%) (E)-2-[4-pentylbenzoyloxy]-5-[6-[2-methoxy-4-(methoxycarbonylvinyl)phenoxy]oxyhexyl]benzoic acid 11-(2-methylacryloyloxy)undecyl ester as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:29]2[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 90.1 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate (26 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 34 mg of the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 2.42-2.48 (m, 3H), 3.22-3.30 (m, 4H), 3.77 (s, 3H), 4.12 (s, 4H), 6.90-7.12 (m, 4H), 7.25-7.32 (m, 3H), 7.48-7.65 (m, 2H).
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:10]=[C:9]([C:11]3[S:15][C:14]([NH:16]C(=O)C)=[N:13][C:12]=3[CH3:20])[CH:8]=[N:7][CH:6]=2)[CH2:4][CH2:3]1>C(O)C>[CH:2]1([C:5]2[N:10]=[C:9]([C:11]3[S:15][C:14]([NH2:16])=[N:13][C:12]=3[CH3:20])[CH:8]=[N:7][CH:6]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)Nc1nc(C)c(-c2cncc(C3CC3)n2)s1
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1cncc(C2CC2)n1

Procedure:
Concentrated hydrochloric acid (0.4 ml) is added to N-[5-(6-cyclopropyl-pyrazin-2-yl)-4-methyl-thiazol-2-yl]-acetamide (120 mg) in ethanol (9 ml) at room temperature and the mixture is heated at reflux for 18 hours. The cooled reaction mixture is evaporated, neutralized with aqueous sodium hydrogen carbonate and extracted with 10% methanol in DCM. The combined organic extracts are dried over sodium sulphate and evaporated to give the title compound. HPLC/MS: retention time 0.93 minutes, M+H 233.3.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:16][CH:17]=[CH2:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C(OC(=O)N[C@H]1C[CH:43]=[CH:42][C@@H:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:40](C)[C:39]1=O)(C)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][N:40]([CH:41]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH:42]=[CH2:43])[C:13]([C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][CH:17]=[CH2:18])=[O:15]
Reactant: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC=C[C@H]1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)N(C)C(C=C)c1ccccc1
Temperature: -20 °C
Reaction time: 4 h
Yield: 133.8 %

Procedure:
To a solution of (2R)-2-{[(benzyloxy)carbonyl]amino}pent-4-enoic acid (3a) (1.1 g) in DCM (5 mL) at −20° C. under N2 was added a mixture of EDAC.HCl (1.02 g) and DMAP (12 mg) in DCM (8 mL) portionwise. Methyl(1-phenylprop-2-en-1-yl)amine (1d) (650 mg) in DCM (3 mL) was then added dropwise to the reaction mixture. The reaction mixture was stirred for 1.5 h at −20° C. and 4 h at RT, then diluted with DCM (100 mL) and washed with 0.2 N HCl, saturated NaHCO3, brine, dried (Na2SO4), filtered, and evaporated. The crude product was purified via flash chromatography (20% EtOAc/hexanes) to give the desired product as a viscous oil (1.04 g, 63%). 1H NMR (300 MHz, CDCl3) δ 2.38-2.47 (m, 1H), 2.50-2.59 (m, 1H), 2.66-2.82 (m, 3H-diastereomer/rotamer mixture), 4.77-4.80 (m, 1H), 5.08-5.17 (m, 4H), 5.22-5.48 (m, 2H), 5.69-5.82 (m, 2H), 6.03-6.14 (m, 1H), 6.39-6.43 (m, 1H), 7.25-7.35 (m, 10H). MS APCI, m/z=379 (M+1). LC/MS 2.72 min., Method A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]([OH:27])=O)[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:10][CH2:9]1.Cl.[NH2:29][C@@H:30]([C:35]([NH2:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33]>>[NH2:37][C:35]([C@H:30]([NH:29][C:25]([C:4]1[CH:5]=[N:6][C:7]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][O:16][C:15]3=[O:24])[CH2:10][CH2:9]2)=[C:2]([Cl:1])[CH:3]=1)=[O:27])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:36]
Reactant: O=C(O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Reactant: CC(C)C[C@@H](N)C(N)=O
Agent: Cl
Product: CC(C)C[C@@H](NC(=O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1)C(N)=O

Procedure:
The title compound was prepared from the product of example 148 step (i) (0.15 g) and (R)-leucinamide hydrochloride (0.07 g) according to the method of example 115, step (i). Yield 0.05 g as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:5]([OH:17])=[CH:4][CH:3]=1.C1C(=O)N([Cl:25])C(=O)C1>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[Cl:25])=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:5]([OH:17])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc(Cl)nc1-c1cc2ccccc2[nH]1
Solvent: CC(C)=O
Product: Oc1ccc(Cl)nc1-c1[nH]c2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A mixture of 6-chloro-2-(1H-indol-2-yl)pyridin-3-ol (244 mg, 1 mmol, described in Example 1) and NCS (160 mg, 1.2 mmol) in Acetone (2 mL) was stirred at room temperature for 1 hour. The mixture was then concentrated and purified using prep-TLC (petroleum ether:EtOAc=2:1) to provide 6-chloro-2-(3-chloro-1H-indol-2-yl)pyridin-3-ol (180 mg, yield: 64.7%). 1H-NMR (CDCl3, 400 MHz) δ 9.03 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.15˜7.36 (m, 5H), 6.20˜6.40 (br s, 1H). MS (M+H)+: 279/281.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]1[NH2:19].C(N(CC)CC)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[NH2:19])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: NC1CCCCC1Nc1nc(Cl)nc2[nH]ccc12
Yield: 63.2 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.53 mmol), cis-1,2-diaminocyclohexane (0.107 mL, 0.91 mmol) and triethylamine (0.150 mL, 1.08 mmol) in nBuOH (4 mL) was stirred at 70° C. for 4 h. It was then purified by HPLC to give N1-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohexane-1,2-diamine as a solid (89 mg).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][C:26](=O)[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.[CH3:31][NH:32][CH3:33]>>[F:30][C:2]1([F:1])[CH2:3][CH2:4][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][CH:26]([N:32]([CH3:33])[CH3:31])[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:6][CH2:7]1
Reactant: O=C1CCC(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1
Reactant: CNC
Product: CN(C)C1CCC(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 133 using 6-chloro-2-(3-oxo-cyclopentyl)-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexyl methyl)-amide, and dimethylamine. 1H NMR (400 MHz, DMSO-d6): δ 8.76 (d, J=6.2 Hz, 1H), 8.13 (t, J=5.6 Hz, 1H), 8.11-7.96 (m, 1H), 7.79-7.77 (m, 2H), 7.59 (d, J=8.6 Hz, 1H), 3.41-2.85 (m, 1H), 2.84-2.50 (m, 1H), 2.50-2.49 (m, 2H), 2.48-2.46 (m, 6H), 2.25-2.07 (m, 1H), 2.01-1.91 (m, 4H), 1.90-1.85 (m, 5H), 1.73-1.69 (m, 4H). m/z: 466.3 [M+H]+
Reaction SMILES: [CH3:1][C:2]1([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:6](=[O:7])[NH:5][C:4](=[O:8])[NH:3]1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:6](=[O:7])[N:5]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:4](=[O:8])[NH:3]1
Reactant: CC(C)(C)OC(=O)CC1(C)NC(=O)NC1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC1(C)NC(=O)N(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of tert-butyl 2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetate (100 mg, 0.44 mmol) in DMF (1 mL) was added potassium carbonate (120 mg, 0.88 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (110 mg, 0.48 mmol) and the reaction mixture stirred at rt overnight. The mixture was diluted with EtOAc (30 mL) and washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexane followed by 10% MeOH/DCM to give Compound 26c (102 mg, 75% yield). 1H NMR (400 MHz, CDCl3) δ 6.12 (br. s., 1H), 4.14 (q, J=8.5 Hz, 2H), 2.78-2.62 (m, 2H), 1.52 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[C:8]([OH:26])([CH3:25])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=O.[NH3:27].CO>C1COCC1>[OH:26][C:8]1([CH3:25])[C:7]2[S:6][C:5]([C:3]([NH2:27])=[O:2])=[N:14][C:13]=2[C:12]2[CH:15]=[C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])[CH:17]=[CH:18][C:11]=2[O:10][CH2:9]1
Reactant: N
Reactant: COC(=O)c1nc2c(s1)C(C)(O)COc1ccc(C#CC(C)(C)O)cc1-2
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(C)(O)CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (312 mg, 0.84 mmol) in THF (8 mL) at room temperature, NH3/CH3OH (self-made, 8 mL) was added. The mixture was stirred at room temperature for 3 h, and then concentrated to give a residue which was purified by flash column chromatography (silica gel, EtOAc in hexane from 0 to 50%) to give 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as an off-white solid (212 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 8.57 (d, J=2.0 Hz, 1H), 8.47 (s, 1H), 7.90 (s, 1H), 7.31 (dd, J1=8.3 Hz, J2=2.1 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.26 (s, 1H), 5.46 (s, 1H), 4.21 (d, J=11.7 Hz, 1H), 4.01 (d, J=11.8 Hz, 1H), 1.57 (s, 3H), 1.49 (s, 6H); LC-MS (ESI & APCI): 359.2 (M+1).