Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[C:18]3=[C:19]4[CH:25]=[CH:24][NH:23][C:20]4=[N:21][CH:22]=[C:17]3[NH:16][C:15]2=[O:26])[C@H:10]([CH3:27])[CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:27][C@H:10]1[C@@H:11]([N:14]2[C:18]3=[C:19]4[CH:25]=[CH:24][NH:23][C:20]4=[N:21][CH:22]=[C:17]3[NH:16][C:15]2=[O:26])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: C[C@@H]1CN(Cc2ccccc2)CC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1CNCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Temperature: 45 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of rel-1-[(3R,4S)-1-benzyl-3-methyl-4-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (125 mg) in ethanol (6.25 mL) was added palladium hydroxide (200 mg). The mixture was stirred under hydrogen gas at 45° C. for 2 hours. The catalyst was filtrated through a pad of Celite. The filtrate was concentrated under reduced pressure to give rel-1-[(3R,4S)-3-methyl-4-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (93 mg) as a white powder.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][C@H:5]([OH:8])[C@@H:4]1[OH:9].[CH3:10][C:11]1([CH3:35])[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[C:17]2[CH:16]=[C:15]([C:23]3[N:24]=[C:25]([N:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)[S:26][CH:27]=3)[CH:14]=[CH:13][C:12]1=2.Cl>>[CH3:10][C:11]1([CH3:35])[CH2:20][CH2:19][C:18]([CH3:21])([CH3:22])[C:17]2[CH:16]=[C:15]([C:23]3[N:24]=[C:25]([N:28]4[CH2:33][CH2:32][CH:31]([NH:2][C@@H:3]5[CH2:7][CH2:6][C@H:5]([OH:8])[C@@H:4]5[OH:9])[CH2:30][CH2:29]4)[S:26][CH:27]=3)[CH:14]=[CH:13][C:12]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(=O)CC4)n3)ccc21
Reactant: N[C@@H]1CC[C@H](O)[C@@H]1O
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N[C@@H]5CC[C@H](O)[C@@H]5O)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously starting from 24 mg (0.16 mmol) of (1S,2R,3R)-3-aminocyclopentane-1,2-diol hydrochloride and 60 mg (0.16 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]-piperidin-4-one. The product is in the form of the hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23](Cl)=[O:24])[CH:19]=[CH:20][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:23](=[O:24])[CH2:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: COc1ccc(CCN)cc1OC
Product: COc1cccc(CC(=O)NCCc2ccc(OC)c(OC)c2)c1

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine with 3-methoxyphenyl acetyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][S:16][C:15]=2[C:19](OC)=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][S:16][C:15]=2[CH2:19][OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccsc2CO)CC1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
A solution of 4-(2-methoxycarbonylthiophen-3-yl)piperidine-1-carboxylic acid t-butyl ester (2.4 g, 7.4 mmol, 1.0 eq.) in THF (20 mL) was degassed and purged with nitrogen (2×). Borane dimethyl sulfide complex (35 mL, 70 mmol, 110.8 eq.) was added at room temperature and the mixture was heated to reflux overnight. The mixture was allowed to cool to room temperature and MeOH (20 mL) was slowly added. The mixture was then concentrated under vacuum. The addition of MeOH (20 mL) and concentrating was repeated two additional times. The product was applied onto a silica gel column and purified by chromatography with PE/EtOAc (10:1). The product was then purified by preparative HPLC to yield the title compound (1.5 g) as a yellow oil, which gradually solidified.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N:15]([CH2:20][CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:22]=[C:23]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:24]([C:25](O)=[O:26])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[CH2:36][N:37]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN>ClCCl.O>[CH2:1]([O:8][C:9]1[C:14]([N:15]([CH2:20][CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:22]=[C:23]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:24]([C:25]([NH:37][CH3:36])=[O:26])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)O)c2cc1OCc1ccccc1)S(C)(=O)=O
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1OCc1ccccc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(Benzyloxy)-6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.11 g, 0.22 mmol, 1 eq), EDCI.HCl (0.048 g, 0.25 mmol, 1.1 eq), HOBT (0.036 g, 0.27 mmol, 1.2 eq), DIPEA (0.12 ml, 0.68 mmol, 3 eq) were dissolved in dichloromethane and the reaction was stirred at room temperature for 10 minutes. Then Methylamine (1M in THF, 0.6 ml, 5 eq) was added to the above solution and the reaction was stirred at room temperature for 14 h. Finally, the mixture was diluted with water and the product was extracted with dichloromethane. The organic layer was washed with water, dried and concentrated. Yield: 0.1 g (90%). 1HNMR (400 MHz, DMSO-d6): δ 1.06 (t, J=7.12 Hz, 3H), 2.77 (s, 3H), 3.00 (s, 3H), 3.62 (br m, 2H), 5.30 (s, 2H), 7.30-7.32 (m, 3H), 7.33 (d, J=5.8 Hz, 1H), 7.40-7.43 (m, 2H), 7.53-7.55 (m, 2H), 7.81 (t, J=3.52 Hz, 1H), 7.95 (s, 2H), 8.88 (s, 1H). LCMS: (ES+) m/z=497.0 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=1.CCN(CC)CC>C(Cl)Cl>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=1
Reactant: OCc1ccc(CNc2ccccn2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1ccc(CNc2ccccn2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 30.8 %

Procedure:
To a solution of oxalyl chloride (0.9 ml, 10.32 mmol) in CH2Cl2 (15 ml) at −78° C. was added a solution of DMSO (1.5 ml, 21.11 mmol) in CH2Cl2 (10 ml) and the mixture allowed to stir for 20 min. at −78° C., after which [4-(Pyridin-2-ylaminomethyl)-phenyl]-methanol (1.1 g, 5.13 mmol) in CH2Cl2 (10 ml) was added dropwise. Stirring was continued for 2 hours and then Et3N (2.9 ml, 21.30 mmol) was added dropwise. The cooling bath was removed, stirring was continued for 3 h, and the mixture was diluted with 300 mL ethyl acetate, washed with sat. NaHCO3, brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel, using 30% ethyl acetate in CH2Cl2, gave the title compound (335 mg, 31%) as a pure white solid.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH3:19])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[CH3:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCCCCCCCCCCCCBr
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCC[C@@H](O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 4 (380 mg, 1.50 mmol) and 1-bromononadecane (1.30 g, 3.75 mmol), alcohol 49 was obtained as a colorless oil (349 mg, 45% yield).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=2)[CH:8]=[CH:7][N:6]=1.CC1CCCO1.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH2:42]S(C2C=CC=CC=2)(=O)=O)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][CH:29]=1)#[N:27]>O>[C:37]([O:36][C:35](=[O:41])[N:34]([C:31]1[CH:30]=[CH:29][C:28]([C:26]#[N:27])=[CH:33][CH:32]=1)[CH2:42][C:13]1[C:14](=[O:17])[CH2:15][CH2:16][C:12]=1[NH:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:4]([F:3])([F:18])[F:19])[CH:10]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: O=C1C=C(Nc2ccnc(C(F)(F)F)c2)CC1
Reactant: CC(C)(C)OC(=O)N(CS(=O)(=O)c1ccccc1)c1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC1=C(Nc2ccnc(C(F)(F)F)c2)CCC1=O)c1ccc(C#N)cc1

Procedure:
Sodium hydride (60% in mineral oil, 895 mg, 22.4 mmol) is added in portions to a mixture of 3-(2-(trifluoromethyl)pyridin-4-ylamino)cyclopent-2-enone (intermediate 17, 4.52 g, 18.7 mmol) and 2-methyltetrahydrofuran (30 mL). After 30 min tert-butyl (4-cyano-phenyl)(phenylsulfonyl)methylcarbamate (6.90 g, 18.5 mmol) is added, and mixture is stirred at room temperature for 30 min Water is added, and the phases are separated. The organic phase is dried over Na2SO4 and concentrated under reduced pressure. Yield: 9.20 g; ESI mass spectrum [M+H]+=473; Retention time HPLC: 1.09 min (Z018_504).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[S:6][CH:7]=[C:8]([CH:9]([P:23]([CH3:26])(=[O:25])[OH:24])[C:10](=[O:22])[NH:11][CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[C:4]=2[CH:3]=1.[OH-].[OH:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34]>CO>[OH:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34].[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[S:6][CH:7]=[C:8]([CH:9]([P:23]([CH3:26])(=[O:24])[O-:25])[C:10](=[O:22])[NH:11][CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[C:4]=2[CH:3]=1
Reactant: CP(=O)(O)C(C(=O)NC=Cc1ccc(F)c(F)c1)c1csc2ccc(Cl)cc12
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: CO
Product: CP(=O)([O-])C(C(=O)NC=Cc1ccc(F)c(F)c1)c1csc2ccc(Cl)cc12
Temperature: 64 °C
Reaction time: 1 h

Procedure:
A 250 mL three-necked round-bottomed flask was charged with {(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinic acid (20.0 g, 42.2 mol) and methanol (150 mL), under nitrogen. To the resulting slurry was then added 45% by wt. of choline hydroxide in methanol (12.8 mL, 45.3 mol), in one portion. Shortly after the addition, a homogeneous clear solution was obtained. The solution was aged at room temperature for about 1 hour, then clarified by filtration through a medium sintered glass filter. The resulting filtered solution was concentrated by distillation (at a temperature of about 63-65° C.) to a residual volume of about 55-60 mL. While at the elevated temperature, EtOAc (140-150 mL) was added by an addition funnel over a period of about 40 minutes, while maintaining a temperature of about 63-65° C. The resulting clear solution was seeded, then cooled slowly under moderate agitation to ambient temperature. The resulting slurry was then aged overnight, cooled to about 5-10° C. and aged at this temperature for about 2 hours. The resulting solid was collected by filtration, rinsed with cold EtOAc (40 mL, 2C) and dried in a vacuum oven at 50° C., overnight to yield the title compound as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9](O)=[O:10])=[CH:4][CH:3]=1.[NH3:19]>O=S(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([NH2:19])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: N
Solvent: O=S(Cl)Cl
Product: NC(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A suspension of 2,2-bis-(4-chloro-phenyl)-acetic acid (0.50 g, 1.8 mmol) in SOCl2 (5 mL) was heated at reflux for 1 h. The mixture was concentrated, and the residue was azeotroped with toluene (3×). The crude acid chloride was stirred in DCM (10 mL) at rt and treated with NH3 (0.5 M in dioxane, 14 mL, 7.5 mmol). After 1 h, the reaction mixture was concentrated, and the residue was diluted with satd. aq. NaHCO3 and extracted with DCM (3×). The combined organics were dried (Na2SO4) and concentrated to provide the amide as a white solid (0.50 g, 100%). The amide was used without further purification. 1H NMR (400 MHz, CDCl3): 7.35-7.28 (m, 4H), 7.23-7.17 (m, 4H), 5.69 (br s, 1H), 5.53 (br s, 1H), 4.87 (s, 1H).
Reaction SMILES: Br[C:2]1[N:3]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:4]2[N:5]=[C:6]([NH2:12])[NH:7][C:8](=[O:11])[C:9]=2[N:10]=1.NC(N)=[S:21]>CN(C=O)C>[NH2:12][C:6]1[NH:7][C:8](=[O:11])[C:9]2[NH:10][C:2](=[S:21])[N:3]([CH2:13][C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[C:4]=2[N:5]=1
Reactant: NC(N)=S
Reactant: Nc1nc2c(nc(Br)n2Cc2cccs2)c(=O)[nH]1
Solvent: CN(C)C=O
Product: Nc1nc2c([nH]c(=S)n2Cc2cccs2)c(=O)[nH]1

Procedure:
A mixture of 8-bromo-9-[(2-thienyl)methyl]guanine (see Example 5) (2.0 g; 6.13 mmol), DMF (250 ml), and thiourea (0.93 g; 12.26 mmol) was heated under reflux for 20 hours and then the solvent was evaporated to dryness under reduced pressure. The residue was dissolved in 1N NaOH, treated withcharcoal, filtered, and acidified with glacial AcOH to give a pale yellow solid. Analytical sample was prepared by repeating the purification process, yield 709 mg; mp>280° C.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:16]2[C:11](=[C:12]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[C:13]([O:19]C)=[C:14]([O:17]C)[CH:15]=2)[CH:10]=[C:9]([CH3:30])[C:8]=1[C:31]1[C:40]([CH3:41])=[CH:39][C:38]2[C:33](=[CH:34][C:35]([O:53]C)=[C:36]([O:51]C)[C:37]=2[CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[C:32]=1[O:55]C.Cl>C(Cl)Cl>[CH3:41][C:40]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35]([OH:53])[C:36]([OH:51])=[C:37]2[CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)=[C:32]([OH:55])[C:31]=1[C:8]1[C:7]([OH:6])=[C:16]2[C:11](=[CH:10][C:9]=1[CH3:30])[C:12]([CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1)=[C:13]([OH:19])[C:14]([OH:17])=[CH:15]2
Reactant: COc1cc2c(OC)c(-c3c(C)cc4c(CCc5ccc(C)cc5)c(OC)c(OC)cc4c3OC)c(C)cc2c(CCc2ccc(C)cc2)c1OC
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(CCc2c(O)c(O)cc3c(O)c(-c4c(C)cc5c(CCc6ccc(C)cc6)c(O)c(O)cc5c4O)c(C)cc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
2.1 mL of BBr3 solution (5.56 g, 22.2 mmol) was added dropwise into a solution of 15f (1.23 g, 1.76 mmol) in 60 mL of anhydrous CH2Cl2 at −78° C. Stirring was continued at −78° C. for 1 h, 0° C. for 1 h, and ambient temperature for 1 h, respectively. 300 grams of ice containing 30 mL of 6M HCl was added to the mixture and stirred for 0.5 h at room temperature. The aqueous layer was extracted with dichloromethane (3×100 mL). The combined organic layer was washed with water, brine and dried over MgSO4. The solvent was concentrated in vacuo and the residue was purified by C-18 column chromatography (H2O/Acetonitrile) to give 1.1 g of compound 2f (90%) as white solid. Yield, 45%; NMR (600 MHz, CD3OD) δ 7.45 (s, 2H), 7.34 (s, 2H), 7.20 (d, J=7.2 Hz, 4H), 7.08 (d, J=7.2 Hz, 4H), 3.27 (m, 4H), 2.87 (m, 4H), 2.31 (s, 6H), 2.03 (s, 6H). HPLC purity 96.6%, tR=17.00 min (Method A). HRMS calcd for C40H38O6 615.2741 (M+H). found 615.2720.
Reaction SMILES: [CH2:1]=[CH:2][N:3]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4]1.N(C(C)(C)C#N)=N[C:11](C)(C)C#N.[C:21]([O:25][CH2:26][CH2:27][CH2:28]C)(=[O:24])[CH:22]=[CH2:23].CCCCCC>CN(C)C=O>[CH:2]([N:3]1[CH2:4][CH2:5][CH2:6][C:7]1=[O:8])=[CH2:1].[C:21]([O:25][CH:26]([CH2:27][CH3:28])[CH3:11])(=[O:24])[CH:22]=[CH2:23]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: C=CC(=O)OCCCC
Agent: C=CN1CCCC1=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=CC(=O)OC(C)CC
Temperature: 60 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
Along with 228 mg (0.08 mmol) of poly(1-vinyl-2-pyrrolidone) macroinitiator prepared in Example 67, 3.3 mg (0.02 mmol) of 2,2′-azobis(isobutyronitrile) and 1.04 g (8.1 mmole) of n-butyl acrylate (same as above) were placed into a glove box with the inside air replaced by nitrogen, followed by stirring at 60° C. for 6 hours. After the completion of the reaction, the reaction mixture was dissolved in 5 ml of N,N-dimethylformamide (DMF), and the solution was then poured into 300 ml of hexane which was being stirred. The resulting polymer precipitate was collected by suction filtration and dried to obtain block copolymer of poly(1-vinyl-2-pyrrolidone-b-n-butyl acrylate) (yield 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH3:21][C:22]1[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28]O)=[CH:24][CH:23]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:28][CH2:27][O:26][C:25]2[CH:30]=[CH:31][C:22]([CH3:21])=[CH:23][CH:24]=2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(OCCO)cc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc(C)cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(4-methylphenoxy)ethanol (1.15 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material was purified by HPLC (dichloromethane-hexane; 4:1) and crystallized from diethyl ether-hexane to provide 0.83 g of 4-[[2-(4-methylphenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 105°-107° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:1]([NH:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:20]/[N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(NCc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(NCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 96.6 %

Procedure:
A mixture of 4-benzylamino-benzaldehyde (5 g, 23.7 mmol) described in Manufacturing Example 68-1-1, nitromethane (2.55 mL, 47.7 mmol), ammonium acetate (2.74 g, 35.6 mmol) and acetic acid (50 mL) was stirred for 6 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (5.82 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[O:17].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[F:59][C:60]1[CH:65]=[CH:64][C:63]([NH2:66])=[C:62]([NH2:67])[CH:61]=1>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:66][C:63]1[CH:64]=[CH:65][C:60]([F:59])=[CH:61][C:62]=1[NH2:67])=[O:25])=[O:17]
Reactant: Nc1ccc(F)cc1N
Reactant: O=C(O)CCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1cc(F)ccc1NC(=O)CCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.9 %

Procedure:
6-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)hexanoic acid (396 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-fluoro-o-phenylenediamine (151 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (373 mg, 74% yield) as a brown solid. 1H NMR (DMSO-d6)δ1.36 (m, 2H, CH2), 1.59 (m, 4H, CH2), 2.30 (t, J=8.0 Hz, 2H, CH2CO), 3.28 (t, J=8.0 Hz, 2H, NCH2), 5.12 (s, 2H, benzene-NH2), 6.26 (t, J=8.0 Hz, 1H, Ar—H), 6.46 (d, J=8.0 Hz, 1H, Ar—H), 6.87 (m, 1H, Ar—H), 7.12 (m, 3H, Ar—H), 7.64 (m, 1H, Ar—H), 7.73 (s, 0.6×1H, vinyl-H), 7.83 (m, 1H, Ar—H), 7.94 (m, 1H, Ar—H), 8.16 (s, 0.4×1H, vinyl-H), 8.57 (m, 1H, Ar—H), 9.02 (s, 1H, benzene-NH), 10.68 (s, 1H, CONH). LC-MS (m/z) 505 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(#N)C>[C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: IC1CCCC1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(C2CCCC2)C1

Procedure:
Pyrrolidin-3-yl-carbamic acid tert-butyl ester (8) (0.20 g, 1.07 mmol, 1 equiv), iodo-cyclopentane (0.253 g, 1.29 mmol, 1.20 equiv) and triethylamine (0.28 g, 2.15 mmol, 2.00 equiv) were dissolved in acetonitrile (25 mL). The solution was heated to reflux until TLC indicated completion of the reaction. The solvent was evaporated under reduced pressure to yield the title compound. (0.25 g, 1.00 mmol, quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[F:22][C:23]1[C:24]([CH3:32])=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CO.CN(C)C=O>[F:22][C:23]1[C:24]([CH3:32])=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)=[O:27]
Reactant: Cc1c(F)cccc1C(=O)O
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1c(F)cccc1C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 30.9 %

Procedure:
Preparation of example 40 from the title compound of Example 7 (0.030 g, 0.11 mmol), 3-Fluoro-2-methyl-benzoic acid (0.025 g, 0.16 mmol), triethylamine (0.077 mL, 0.44 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (63 mg, 0.16 mmol) and N,N-dimethylformamide (0.05 M, 2.0 mL) was carried out analogously to Example 11. Silica gel chromatography (95:5 CH2Cl2/methanol) afforded the title compound (14 mg) as a yellow powder in 33% yield.