Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH2:22][OH:23])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:24]([C:28]1[CH:29]=[C:30]([CH2:39][CH2:40][C:41](O)=[O:42])[CH:31]=[C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]=1[OH:34])([CH3:27])([CH3:26])[CH3:25].C1(C)C(C)=CC=CC=1>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4].O>[C:35]([C:32]1[CH:31]=[C:30]([CH2:39][CH2:40][C:41]([O:23][CH2:22][CH2:21][NH:20][C:18](=[O:19])[CH2:17][CH2:16][C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[CH:8]=2)=[O:42])[CH:29]=[C:28]([C:24]([CH3:26])([CH3:25])[CH3:27])[C:33]=1[OH:34])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)c1cc(CCC(=O)NCCO)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1cc(CCC(=O)NCCOC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O

Procedure:
A mixture of 32 g (0.1 mole) of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-(2-hydroxyethyl)propionamide, 27 g (0.1 mole) of 3(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid, 1 g Tyzor TBT catalyst and 100 ml xylene was refluxed at 150° until evolution of water ceased. In the course of four hours, two ml water was collected in the Stark & Dean trap. The xylene was removed by vacuum stripping. The title compound (54 g) was recrystallized from a toluene/hexane mixture. It melted at 151°-154° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[NH:14][C:15](=[O:19])[CH2:16][S:17][CH:18]=1.O>CC(C)=O>[OH:9][CH:16]1[C:15](=[O:19])[NH:14][C:13]([CH3:12])=[CH:18][S:17]1
Reactant: CC1=CSCC(=O)N1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CC(C)=O
Product: CC1=CSC(O)C(=O)N1
Reaction time: 2 h
Yield: 46.9 %

Procedure:
m-Chloroperbenzoic acid (0.216 g) was added to 5-methyl-2H-1,4-thiazin-3(4H)-one (0.129 g) in dry acetone (4 ml) under ice-cooling and the mixture was stirred for 2 hours. Water was added to the mixture and the solution was stirred for 30 minutes. Then, the reaction mixture was further stirred at ambient temperature for 3 hours. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel (Wakogel C-200) column, using ethyl acetate-n-hexane (=2:1) as an eluant to give 2-hydroxy-5-methyl-2H-1,4-thiazin-3(4H)-one (0.068 g, yield 46.9%) as white crystals.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:6]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:10][O:9][C:7]([C:4]1[S:3][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)=[O:8]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(Br)s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccccc2)s1
Temperature: 80 °C
Reaction time: 18 h
Yield: 83.8 %

Procedure:
To a suspension of 2-bromo-5-methoxycarbonylthiophene (1.11 g) and phenylboronic acid (0.79 g) and tetrakis(triphenylphosphine)-palladium (289 mg) in 1,2-dimethoxyethane (10 ml) was added an aqueous solution of sodium carbonate (2M, 6.5 ml) followed by stirring at 80° C. for 18 hours. The mixture was diluted with dichloromethane and washed with water and brine. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with methanol. The resulting precipitate was collected by filtration, washed with methanol and diisopropyl ether and dried to give 2-methoxycarbonyl-5-phenylthiophene (918 mg, 84.2%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:4]2[N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=1[C@H:48]1[CH2:52][CH2:51][CH2:50][NH:49]1.C(N(C(C)C)CC)(C)C>O.CN(C=O)C>[F:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=1[C@H:48]1[CH2:52][CH2:51][CH2:50][N:49]1[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:4]2[N:3]=1
Reactant: N#Cc1cnn2ccc(O)nc12
Reactant: Fc1ccc(F)c([C@H]2CCCN2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A flask was charged with the product from Step A (2.80 g, 17.5 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (9.28 g, 21.0 mmol) and dry DMF (35 mL). The suspension was stirred at ambient temperature for 2 minutes and (R)-2-(2,5-difluorophenyl)pyrrolidine (Preparation A, 3.84 g, 21.0 mmol) and diisopropylethylamine (6.78 g, 62.5 mmol) were sequentially added (mild exotherm). The mixture was stirred at ambient temperature for 3 hours and poured into H2O (175 mL). The mixture was extracted with 50% EtOAc-hexanes and the combined organic fractions were washed sequentially with 1M HCl, H2O, 1M Na2CO3 and saturated NaCl. The solution was dried over MgSO4/activated carbon and filtered through a short SiO2 plug (350 mL course frit funnel, ¼ full of SiO2, capped with a layer of MgSO4) using 50% EtOAc-hexanes for elution. The solution was concentrated to give the title compound as a brittle white foam that was crushed to a flowing white solid and dried in vacuum (5.50 g, 97%). MS (apci) m/z=326.2 (M+H).
Reaction SMILES: [O-]CC.[Na+].[NH3:5].Cl.Cl[CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][CH2:12]Cl.C(=O)=O>C(O)C.C(OCC)C>[CH2:14]([N:10]1[CH2:11][CH2:12][NH:5][CH2:8][CH2:9]1)[CH2:15][CH2:16][CH3:17]
Reactant: N
Reactant: CCCCN(CCCl)CCCl
Agent: CC[O-]
Agent: Cl
Agent: O=C=O
Solvent: CCO
Solvent: CCOCC
Product: CCCCN1CCNCC1
Temperature: 60 °C

Procedure:
A solution (447 cc.) of sodium ethoxide in ethanol of concentration 1.34 moles per liter, followed by a solution (1,305 cc.) of ammonia in ethanol of concentration 4.6 moles per liter, are added to a suspension of N,N-bis(2-chloroethyl)butylamine hydrochloride (140.7 g.) in ethanol (750 cc.). The reaction mixture is then heated at a temperature of about 60° C. for 1 hour, whilst keeping the ammonia refluxing by means of a condensor containing solid carbon dioxide. The ammonia is then allowed to dissipate, and the reaction mixture is cooled to a temperature of about 20° C. under a stream of nitrogen. A solution (894 cc.) of sodium ethoxide in ethanol of concentration 1.34 moles per liter is then added. The sodium chloride which precipitates is filtered off and then washed with ethanol (150 cc.). The filtrate is concentrated to dryness under reduced pressure and the residue obtained is taken up in diethyl ether (300 cc.). The insoluble product is filtered off and washed with diethyl ether (60 cc.). The filtrate is concentrated to dryness and then distilled under reduced pressure. 1-t.-Butylpiperazine (8.8 g.), which boils at 85°-86° C. under a pressure of 28 mm. Hg, is thus obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[Cl:52][C:48]1[CH:47]=[C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:51]=[CH:50][CH:49]=1
Reactant: [O-]B([O-])Oc1cccc(Cl)c1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4cccc(Cl)c4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.1 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 3-chlorophenyl borate (108 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 10 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(3-chlorophenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 116) (64 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:49]([O:53][C:54]([CH2:56][O:57][CH2:58][C@H:59]([NH2:70])[C:60]1[NH:64][C:63]2[CH:65]=[CH:66][C:67]([Cl:69])=[CH:68][C:62]=2[N:61]=1)=[O:55])([CH3:52])([CH3:51])[CH3:50].ClCl>O1CCCC1.ClCCl.CO>[C:49]([O:53][C:54]([CH2:56][O:57][CH2:58][C@H:59]([NH:70][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[C:2]([CH3:1])[CH:3]=1)[C:60]1[NH:64][C:63]2[CH:65]=[CH:66][C:67]([Cl:69])=[CH:68][C:62]=2[N:61]=1)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: CC(C)(C)OC(=O)COC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C(=O)N[C@@H](COCC(=O)OC(C)(C)C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 82 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (R)-2-(C-tert-butoxycarbonylmethyloxy)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 82%; Rf value: 0.70 (silica gel; dichloromethane/methanol=95:5); C28H33ClN4O5 (541.05); mass spectrum: (M+H)+=541/543 (chlorine isotope) and (M−H)−=539/541 (chlorine isotope).
Reaction SMILES: CNC1(C2C=CC=CC=2Cl)C(=O)CCCC1.CC1C=CC=C(C)C=1NC1SCCCN=1.CC(C1C=CC2SC3C=CC=CC=3N(CCCN(C)C)C=2C=1)=O.[CH:55]1[C:60]([OH:61])=[C:59]([OH:62])[CH:58]=[C:57](O)[C:56]=1[CH2:64][CH2:65][NH2:66].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>>[NH2:66][CH2:65][CH2:64][C:56]1[CH:57]=[CH:58][C:59]([OH:62])=[C:60]([OH:61])[CH:55]=1
Reactant: NCCc1cc(O)c(O)cc1O
Agent: CC(=O)c1ccc2c(c1)N(CCCN(C)C)c1ccccc1S2
Agent: CNC1(c2ccccc2Cl)CCCCC1=O
Agent: Cc1cccc(C)c1NC1=NCCCS1
Product: NCCc1ccc(O)c(O)c1
Reaction time: 0.08 h

Procedure:
Rats were anesthetized with a 1.0 ml/kg intramuscular injection of a mixture of ketamine (33 mg/ml), xylazine (1.7 mg/ml), and acepromazine (10 mg/ml) and positioned in a Kopf stereotaxic instrument. A total of 12 μg of 6-OHDA (6 μl volume at a concentration of 2 μg/μl dissolved in 0.9% saline containing 0.2 μg/μl ascorbic acid) were infused at a rate of 1.0 μl/minute and allowed to diffuse for 5 minutes before the infusion cannula was slowly retracted. Infusion coordinates were 4.2 mm posterior to bregma, 1.0 mm lateral from midline, and 7.4 mm ventral to dura.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH2:29][CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.C(N(CC)CC)C.ClC([O:43][CH2:44][CH3:45])=O.[BH4-].[Na+]>O1CCCC1.O>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH:29]([CH2:45][CH2:44][OH:43])[CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: O=C(c1nc2c(s1)CNCC2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1nc2c(s1)CNC(CCO)C2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
The crude product, which had been obtained by the reaction in the same manner as in Example B-32 by using 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (132 mg) and glyoxylic hydrate (82 mg) as starting materials, was suspended in tetrahydrofuran (50 ml). Triethylamine (0.22 ml) and ethyl chloroformate (0.03 ml) were added to the resulting suspension under ice cooling, followed by stirring at room temperature for 15 minutes. To the reaction mixture, sodium borohydride (50 mg) and water (10 ml) were added to the reaction mixture and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane, washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane˜dichloromethane:methanol 100:3), followed by dissolution in saturated hydrochloride in ethanol (1 ml). The resulting solution was then concentrated under reduced pressure. The concentrate was pulverized and washed in ethyl acetate, whereby the title compound (52 mg, 33%) was obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15].[H-].[Na+].[CH3:18]I>COCCOC>[CH3:1][C:2]1([CH3:18])[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15]
Reactant: CI
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C)C2
Temperature: 30 °C

Procedure:
A stirred suspension of 2-methyl-5-methoxy-6,7-dichloro-1-indanone (12.2 g., 0.05 mole) and sodium hydride (1.43 g., 0.06 mole) in anhydrous 1,2-dimethoxyethane (500 ml.) is heated in an inert atmosphere at 80°-85° C. for 1 hour, cooled to 30° C. and treated with methyl iodide (8 ml.). The reaction mixture is refluxed for 15 minutes, then the solvent is distilled at reduced pressure. The crude product is poured into water (500 ml.), extracted into ether, washed with water and dried over magnesium sulfate. After evaporation of the ether the product is crystallized from methylcyclohexane affording 8.2 g. of 2,2-dimethyl-5-methoxy-6,7-dichloro-1-indanone which melts at 142° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([OH:27])[C:14]([C:24](O)=[O:25])=[N:15][C:16]=2[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=[C:10]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH3:50][O:51][C:52](=[O:58])[CH2:53][C:54]1([NH2:57])[CH2:56][CH2:55]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH3:50][O:51][C:52](=[O:58])[CH2:53][C:54]1([NH:57][C:24]([C:14]2[C:13]([OH:27])=[C:12]3[C:17](=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:15]=2)[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:34])[C:10]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:11]3)=[O:25])[CH2:56][CH2:55]1
Reactant: O=C(O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: COC(=O)CC1(N)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CC1(NC(=O)c2nc(-c3cccnc3)c3c(cc(-c4ccccc4)c(=O)n3Cc3ccccc3)c2O)CC1
Reaction time: 16 h
Yield: 5.9 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid (68 mg, 0.15 mmol) and HOBt (33 mg, 0.24 mmol) was dissolved in CH2Cl2 (3 mL). EDC (52 mg, 0.27 mmol) was added, and the resulting mixture was stirred for 10 min. (1-Amino-cyclopropyl)-acetic acid methyl ester HCl salt (40 mg, 0.24 mmol) and Hunig's base (0.1 mL, 0.55 mmol) were added, and the mixture was stirred for 16 h. The mixture was diluted with EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-90% EtOAc/hexanes+1% AcOH) to give 5 mg of the title compound as a yellow solid. MS: (+) m/z 561.34 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].OC1C=NC=CC=1.C1([O:21][C:22](=O)[CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])C=CC=CC=1>C(OCC)(=O)C>[CH2:28]([O:27][C:25]([NH:24][CH2:23][C:22]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:21])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C1CCNCC1
Reactant: O=C(CNC(=O)OCc1ccccc1)Oc1ccccc1
Agent: Oc1cccnc1
Agent: [Na]
Solvent: CCOC(C)=O
Product: O=C(NCC(=O)N1CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
8.5 g. of piperidine and 1.2 g. of the sodium salt of 3-hydroxypyridine are added to 100 ml. of ethyl acetate, and 28.5 g. of benzyloxycarbonylglycine phenyl ester is added thereto with stirring at room temperature, whereupon reaction immediately starts and is complete in 2 hours. The product is worked up as previously described to give an oil which is crystallized from acetone-water. 18.7 g. of N-(benzyloxycarbonylglycyl)-piperidine are obtained (yield: 68%). m.p. 111°-112° C. A single spot is obtained therefrom by thin layer chromatography. An additional 5.9 g. of crystals are obtained from the mother liquor, (yield: 21%). m.p. 109.5°-112° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[NH2:37][OH:38].O>CO.O>[CH3:20][C:19]1[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]2[CH2:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]([NH:37][OH:38])=[NH:26])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: NO
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1cccc(C#N)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1cccc(C(=N)NO)c1
Yield: 87.7 %

Procedure:
To a solution of 3-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzonitrile (0.117 g, 0.31 mmol) in MeOH (3.0 mL)was added Et3N (0.14 mL, 1.00 mmol) followed by NH2OH.H2O (0.070 g, 1.01 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was diluted with water (5 mL) and extracted with CH2Cl2 (5×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2—CH3OH—NH4OH) provided 113 mg (88%) of COMPOUND 71 as a white solid. 1H NMR (CDCl3) δ 1.50-1.72 (m, 3H), 1.94-2.19 (m, 3H), 2.40 (s, 6H), 3.40 (s, 2H), 3.97 (d, 2H, J=9.3 Hz), 5.75 (br s, 2H), 6.37 (d, 1H, J=7.5 Hz), 6.71 (dd, 1H, J=7.5, 7.5 Hz), 6.89 (dd, 2H, J=7.5, 4.8 Hz), 7.19 (d, 1H, J=8.1 Hz), 7.26-7.29 (m, 2H), 7.42 (s, 1H), 8.30 (d, 2H, J=3.9 Hz); ES-MS m/z 416 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:7]=2[CH:6]=1)=[O:4].CN1CCOCC1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl.C1COCC1.CCOC(C)=O.O>[Cl:22][CH2:23][C:24]([NH:14][C:12]1[CH:11]=[CH:10][C:8]2[S:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=2[CH:13]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1cc2cc(N)ccc2s1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1cc2cc(NC(=O)CCl)ccc2s1
Reaction time: 2.5 h

Procedure:
To a solution of 5-amino-benzo[b]thiophene-2-carboxylic acid methyl ester (989 mg, 4.79 mmol) in CH2Cl2/THF (5/5 mL) was added NMM (630 μL, 5.73 mmol) and chloroacetylchloride (415 μL, 5.25 mmol). After stirring 2.5 h, the mixture was diluted with EtOAc and H2O, and the solid was filtered yielding a pale-white solid, which was used without further purification. MS: cal'd (MH+) 284, exp (MH+) 284.
Reaction SMILES: C([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][C@@H:10]([OH:15])[CH2:9]1)(OC(C)(C)C)=O.[C:16]([C:19]1[CH:20]=[C:21](/[CH:24]=[C:25]2\[C:26](=[O:36])[NH:27][C:28]3[C:33]\2=[C:32](I)[C:31]([F:35])=[CH:30][CH:29]=3)[NH:22][CH:23]=1)(=[O:18])[CH3:17]>CN(C=O)C.CCN(CC)CC.CCOC(C)=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>[C:16]([C:19]1[CH:20]=[C:21](/[CH:24]=[C:25]2\[C:26](=[O:36])[NH:27][C:28]3[C:33]\2=[C:32]([C:14]#[C:13][C@@H:12]2[CH2:11][C@@H:10]([OH:15])[CH2:9][NH:8]2)[C:31]([F:35])=[CH:30][CH:29]=3)[NH:22][CH:23]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Reactant: C#C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#C[C@@H]4C[C@@H](O)CN4)c32)c1
Reaction time: 2 h

Procedure:
Using Method C above, (3R,5S)-N-Boc-3-Hydroxy-5-ethynyl-pyrrolidine (240 mg, 1.13 mmol) (Example 99C above) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (150 mg, 0.38 mmol) (Example 90B) using (Ph3P)4Pd (43 mg, 0.04 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-100% EtOAc in hexanes gradient. The resulting intermediate was dissolved in 6 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.4 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the solution was poured in ammonium hydroxide and extracted with a 5:1 (V/V) mixture of EtOAc and DMF. The organic layer was dried over Na2SO4 and concentrated. (Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-[(2S,4R)-(4-hydroxy-pyrrolidin-2-yl)ethynyl]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-10% MeOH in CH2Cl2 gradient and trituration with CH2Cl2. (Yield 50 mg, 35%).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8](=[O:23])[N:9]([CH2:13][C:14]1[CH:19]=[C:18]([CH:20]=[O:21])[CH:17]=[CH:16][C:15]=1[Cl:22])[CH:10]1[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].O>CC#N>[C:3]([O:7][C:8](=[O:23])[N:9]([CH2:13][C:14]1[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[CH:16][C:15]=1[Cl:22])[CH:10]1[CH2:11][CH2:12]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(C=O)ccc1Cl)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(Cc1cc(CO)ccc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
NaBH4 (1.48 g, 37.7 mmol) was added to a sol. of (2-chloro-5-formyl-benzyl)-cyclopropyl-carbamic acid tert-butyl ester (11.7 g, 37.7 mmol) in CH3CN (113 mL) under N2. The mixture was stirred at rt for 1 h, and water (113 mL) was added. The mixture was stirred at rt for 5 min, and extracted with CH2Cl2 (3×). The combined org. layers were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc 7:3) yielded the title compound (6.53 g, 56%). LC-MS: tR=0.96 min; ES+: 297.37.