Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@@H:2]([CH3:18])[C@@H:3]([NH:7][C:8]([O:10][C:11]1([CH3:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:9])[C:4]([OH:6])=[O:5].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH3:17][C:11]1([O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@H:2]2[CH3:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C[C@H](O)[C@@H](NC(=O)OC1(C)CCOCC1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OC1(C)CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 19.2 %

Procedure:
In a round bottomed flask equipped with a magnetic stirrer and a dropping funnel (2R,3S)-3-hydroxy-2-[(4-methyltetrahydropyran-4-yl)oxycarbonylamino]-butanoic acid (0.2 g, 0.77 mmol) was dissolved in anhydrous CH2Cl2 (7 mL). The clear yellow solution was cooled to 0° C., PyBOP (0.48 g, 0.92 mmol) was added, followed by dropwise addition, over a period of 10 min, of Et3N (0.32 mL, 3.85 mmol) solution in anhydrous CH2Cl2 (5 mL). The crude mixture was stirred at 0° C. for 1 h then overnight at rt. The reaction was quenched by addition of 5% NaHCO3 solution (10 mL) and the corresponding mixture was vigorously stirred for 10 min. The two phases were separated and the organic one collected, dried over Na2SO4 and concentrated to dryness to leave an oil, which was purified by typical chromatography eluting with petroleum ether/AcOEt (from 20:80 to 0:100) to give title compound (0.036 g, 19%) as a light yellow oil. MS (ESI) m/z: 244.1 [M−H]+; (ESI) m/z: 242.2 [M−H]−. 1H NMR (DMSO-d6) δ 1.20 (d, J=6.3 Hz, 3H), 1.48 (s, 3H), 1.67 (m, 2H), 1.99 (m, 2H), 3.60 (m, 4H), 4.83 (m, 1H), 5.37 (dd, J=9.3, 6.3 Hz, 1H), 8.12 (d, J=9.3 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10].Br[CH2:23][C:24]1[S:28][C:27]([C:29]#[N:30])=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10])[O:8][CH2:23][C:24]1[S:28][C:27]([C:29]#[N:30])=[CH:26][CH:25]=1
Reactant: N#Cc1ccc(CBr)s1
Reactant: O=C(c1ccc(O)cc1F)N1CCC[C@H]1CN1CCCC1
Product: N#Cc1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)s1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B using (2-Fluoro-4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 5-bromomethyl-thiophene-2-carbonitrile [CAS 134135-41-4]. MS (ES+) m/e 414.2
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[N:15]=[C:14]([C:16]2[S:17][C:18]([CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:19][CH:20]=2)[NH:13][N:12]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:1]([NH:8][CH2:9][C:11]1[N:15]=[C:14]([C:16]2[S:17][C:18]([CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:19][CH:20]=2)[NH:13][N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)c1n[nH]c(-c2ccc(CN3CCCCCC3)s2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CNCc2n[nH]c(-c3ccc(CN4CCCCCC4)s3)n2)cc1
Yield: 18.2 %

Procedure:
10 ml of anhydrous tetrahydrofuran solution containing 594 mg (1.5 mmol) of the compound obtained in Example 76 was added dropwise to 5 ml of anhydrous tetrahydrofuran suspension containing 230 mg (6.0 mmol) of lithium aluminum hydride, and the mixture was heated under reflux for 11 hours. Then, 460 mg (12.0 mmol) of lithium aluminum hydride was added and the mixture was again heated under reflux for 3 days. To the reaction mixture was added sodium sulfate decahydrate, the resulting insoluble matter was removed by filtration. The solvent was evaporated and then the resulting residue was purified by a silica gel column chromatography to give 104 mg of the title compound in its free form. By subjecting a 74 mg portion of this compound to salt formation using 33 mg of fumaric acid and recrystallizing it from methanol, 63 mg of the title compound was obtained.
Reaction SMILES: [C:1]([CH:3]([N:21]([CH3:29])[C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][O:25]1)=[O:23])[C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:11])[S:7][CH:8]=1)#[N:2]>CO.[Ni]>[NH2:2][CH2:1][CH:3]([N:21]([CH3:29])[C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][O:25]1)=[O:23])[C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:11])[S:7][CH:8]=1
Reactant: CN(C(=O)C1CCCO1)C(C#N)c1csc(NC(=O)NCc2cccc(F)c2)n1
Agent: [Ni]
Solvent: CO
Product: CN(C(=O)C1CCCO1)C(CN)c1csc(NC(=O)NCc2cccc(F)c2)n1

Procedure:
Tetrahydro-furan-2-carboxylic acid (cyano-{2-[3-(3-fluoro-benzyl)-ureido]-thiazol-4-yl}-methyl)-methyl-amide (420 mg) was dissolved in MeOH (10 mL) and treated with Raney®-Nickel under a pressurized hydrogen (45 psi) over a couple of hours until all starting materials were consumed. The final product was purified by column chromatography. The product was confirmed by 1H NMR and LC-MS.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[C:8]([C:27]([OH:29])=[O:28])[C:9]([O-:26])=[C:10]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[C:14]([C:22]([OH:24])=[O:23])[C:13]=3[O-:25])[C:4]2=[CH:3][CH:2]=1.[Na+].[Na+].C[C@@H]([C@@H]1[C@@]2(C)[C@@H](O)C[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4C[C@@H](O)[C@H]3[C@@H]2CC1)CCC(O)=O>>[CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[CH:7][C:8]([C:27]([OH:29])=[O:28])=[C:9]([OH:26])[C:10]=2[CH2:11][C:12]2[C:13]([OH:25])=[C:14]([C:22]([OH:24])=[O:23])[CH:15]=[C:16]3[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]3)[CH:6]=1
Reactant: O=C(O)c1cc2ccccc2c(Cc2c([O-])c(C(=O)O)cc3ccccc23)c1[O-]
Agent: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2c(Cc2c(O)c(C(=O)O)cc3ccccc23)c1O

Procedure:
Alternative organic ions in addition to pamoate were investigated to explore the general utility of the present invention. Microparticle formulations were prepared by an oil-in-water emulsion/solvent extraction method. PLGA polymer (MW 24,000, 160 mg) was dissolved in EtOAc (1000 μL). Octreotide acetate (40 mg) was dissolved in BnOH (1000 μL) and added to the polymer solution yielding a homogenous organic phase. The resulting organic phase was combined with a 1% PVA aqueous phase containing 10-20 mM organic acid as its sodium salt to provide an emulsion. The emulsion was collected directly into a 0.3% PVA solvent extraction solution (150 mL) and stirred for four hours to extract EtOAc. Hardened microparticles were collected by filtration, washed with water, air dried and stored at 4° C. This resulted in microparticle formulations with octreotide core loads between 6.8 and 15.3% as measured by RP-HPLC (Table 8). The effects of the tested organic ions on core load are revealing. Formulations AM-AP show no increase in the measured core load relative to control containing sodium pamoate (Formulations AT, AU, AY, Table 8). In contrast formulations AQ-AS, AV-AX and AZ-BB, which employed organic acids ranging from cholic acid to bicyclic aromatics, provided peptide core loads comparable to pamoic acid (Table 8). These results imply that organic acids with appropriate physiochemical properties can be substituted for pamoic acid to produce comparable microparticle formulations.
Reaction SMILES: [H-].[Na+].C1COCC1.[CH2:8]([O:15][CH2:16][CH2:17][OH:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:20]1[C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[N:23]=[C:22]([NH2:29])[N:21]=1>C1COCC1>[CH2:8]([O:15][CH2:16][CH2:17][O:18][C:20]1[C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[N:23]=[C:22]([NH2:29])[N:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nc(Cl)c2c(n1)CCC2
Reactant: OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc2c(c(OCCOCc3ccccc3)n1)CCC2

Procedure:
(S M:Ross, L. O.; Goodman, L.; Baker, B. R. J. Am. Chem. Soc. 1959, 81, 3108) To stirred suspension of NaH (60% 552 mg) in THF 2-benzyloxyethanol (3.38 g, 20 mmol) was slowly added at room temperature. After the addition, 3.28 grams (19.4 mmol) of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in 200 ml THF and added to it and the mixture was refluxed for 3 hours. Then the solvent was removed in vacuo and 100 ml water was added to the residue. The product was extracted with chloroform; washed well with water and dried over anhydrous MgSO4. It was filtered and concentrated. Low melting solid; Yield: 4.2 gram (73%); (M+H) 286.1
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][C:10]3[C:15]([C:16]4([CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.[N:23]#CBr>C(Cl)Cl>[C:22]([N:19]1[CH2:20][CH2:21][C:16]2([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[CH2:9][C:10]3[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17][CH2:18]1)#[N:23]
Reactant: COc1cccc2c1Cc1ccccc1C21CCN(C)CC1
Reactant: N#CBr
Solvent: ClCCl
Product: COc1cccc2c1Cc1ccccc1C21CCN(C#N)CC1

Procedure:
4-Methoxy-1'-methyl-9,10-dihydroanthracene-9-spiro-4'-piperidine (12.6 g.) and cyanogen bromide (5.6 g.) in methylene chloride (250 ml.) are stirred at room temperature for 18 hours. The reaction mixture is evaporated to dryness, and the residue is taken up in chloroform, the solution washed with water and with brine, dried (MgSO4), and evaporated to give a brown oil which is chromatographed rapidly on silica gel. Elution with ethyl acetate affords pure 1'-cyano-4-methoxy-9,10-dihydroanthracene-9-spiro-4'-piperidine as an oil, characterised by the peak at 2200 cm-1 (C≡N stretching) in its infra-red spectrum.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[C:17](#[N:19])C.CI.[C-]#N.[Na+]>O>[N+:14]([C:12]1[CH:13]=[C:8]2[C:9]([C:5]([CH2:4][C:17]#[N:19])=[CH:6][NH:7]2)=[CH:10][CH:11]=1)([O-:16])=[O:15]
Reactant: CN(C)Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Reactant: CC#N
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CI
Product: N#CCc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
To a stirred solution of 44.27 g (0.204 mol) of 6-nitrogramine (12) [Jackson B. Hester J. Org. Chem., 29: 1158 (1964)] in 450 ml of acetonitrile 44.59 g (0.31 mol) of methyl iodide was added at 0-5° C. over a period of an hour. The reaction mixture was stirred at room temperature for three hours, then a solution of 26.6 g (0.543 mol) of sodium cyanide in 225 ml of water added at once. The reaction mixture was heated at 32° C. overnight, cooled to room temperature and the product extracted 3 times with a total of 800 ml of ethyl acetate and 300 ml of water. The combined extracts were washed with water, 1N-HCl solution, a saturated sodium bicarbonate solution, dried on MgSO4 and the solvent evaporated in vacuo. The orange-brown residue (41.3 g) was dissolved in 200 ml of warm ethyl acetate and passed through a small pad of silica gel to produce 28.9 g (70.4%) of (6-nitro-1H-indolyl-3-yl)-acetonitrile (13) as a yellow solid after evaporation of the solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:5].[Br:18]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][Br:18])=[CH:10][CH:11]=1)=[O:5]
Reactant: Cc1ccc(C(=O)c2c(Cl)cccc2Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=C(c1ccc(CBr)cc1)c1c(Cl)cccc1Cl
Yield: 48.2 %

Procedure:
A refluxing mixture of 4-(2,6-dichlorobenzoyl)toluene (12.0 g, 45.2 mmol) and dibenzoylperoxide (90 mg, 0.37 mmol) in benzene (450 ml) was treated in portions with N-bromosuccinimide (8.83 g, 49.6 mmol), refluxed 1.5 hours, cooled, and evaporated to dryness under vacuum. The residue was triturated with diethyl ether (300 ml), filtered, and the filtrate was evaporated to dryness under vacuum. The crude product was chromatographed on a column of silica gel (700 g) eluted with 97:3 (v/v) hexaneethyl acetate to provide 7.49 g (48%) 4-(2,6-dichlorobenzoyl)benzyl bromide, m.p. 126°-130° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl[C:13]([O:15][CH2:16][CH:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14]>C(=O)(O)[O-].[Na+].O1CCCC1>[C:13]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[C:9]([OH:11])=[O:10])([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(C(C(=O)O)C(=O)OCC2c3ccccc3-c3ccccc32)cc1
Reaction time: 4 h
Yield: 56.3 %

Procedure:
4-aminophenyl acetic acid (204 mg, 1.35 mmol) in a 10 mL flask was dissolved in a mixture of 10% aqueous sodium bicarbonate (0.29 mL) and tetrahydrofuran (2.3 mL) then cooled in an ice/water bath. 9-fluorenylmethyl chloroformate (367 mg, 1.42 mmol) was added in small portions over 3 min. After 4 h the cooling bath was removed. After additional 4 h at room temperature, the reaction was extracted with deionized water (2 mL) and ethyl ether (2 mL) and the aqueous layer was brought to pH 4 with dilute HCl and placed in a refrigerator. After 1 h solid was collected by vacuum filtration and washed with deionized water then dried under vacuum to give 284 mg of product (56% yield). Mass spectrum (M+Na)+ calcd for C23H19NO4, 396.1. found, 396.1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[C:4]([O:10][CH2:11][O:12][CH3:13])[CH:3]=1.C(Cl)(Cl)(Cl)[Cl:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:15])=[C:4]([O:10][CH2:11][O:12][CH3:13])[CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COCOc1cc(Cl)ccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCOc1cc(Cl)ccc1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
4.69 g of 4-chloro-2-methoxymethoxybenzyl alcohol [prepared as described in step (b) above] were dissolved in 80 ml of tetrahydrofuran, and then 7.11 g of carbon tetrachloride and 12.14 g of triphenylphosphine were added to the resulting solution. The resulting mixture was stirred at room temperature for 1 hour and then heated under reflux for 2.5 hours. At the end of this time, any insoluble substance was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.38 g (yield 66%) of the title compound as an oily substance.
Reaction SMILES: N[C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:5](=[O:28])[NH:6]2.N(OCCC(C)C)=O.C(=O)([O-])O.[Na+]>O1CCCC1.[Cu](Cl)Cl>[CH3:31][C:30]([CH3:33])([CH3:32])[CH2:29][N:4]1[C:3]2[C:7](=[N:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[N:12]=3)=[N:10][CH:2]=2)[NH:6][C:5]1=[O:28]
Reactant: CC(C)(C)Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CC(C)(C)Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.22 mmol) of the compound from example 120 were initially charged in tetrahydrofuran (10 ml), then 0.21 ml (1.57 mmol) of isoamyl nitrite and 6.0 mg (0.05 mmol) of copper(II) chloride were added, and the mixture was stirred at RT overnight. The reaction mixture was admixed with saturated aqueous sodium hydrogencarbonate solution and extracted twice with ethyl acetate. The collected organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid gradient). This gave 34 mg (34% of theory) of the title compound in solid form.
Reaction SMILES: I[CH:2]1[C:12](=[O:13])[NH:11][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][NH:5][C:4]=2[CH2:3]1.[NH3:14]>>[NH2:14][CH:2]1[C:12](=[O:13])[NH:11][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][NH:5][C:4]=2[CH2:3]1
Reactant: N
Reactant: O=C1NC2=C(CC1I)NC=CC=C2
Product: NC1CC2=C(C=CC=CN2)NC1=O

Procedure:
Thus obtained 3-iodo-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepin-2-one (109 mg) was dissolved in 7 M methanolic ammonia solution (5 mL) at room temperature under argon. When the starting material was consumed, the mixture was evaporated under vacuum, and the residue was purified by silica gel chromatography to obtain 3-amino-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepin-2-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:18])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: C1CCNCC1
Product: O=C(N1CCCCC1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
Added 0.590 g of 4-nitrophenyl 4-(4-nitrophenyl)piperazine-1-carboxylate to 5.0 mL piperidine and stirred at room temperature until complete. HPLC indicated that reaction was complete after 18 hrs by absence of starting material. Material was added to 15 mL ice water and precipitate formed which was filtered to obtain (4-(4-nitrophenyl)piperazin-1-yl)(piperidin-1-yl)methanone as a yellow powder. Product was allowed to dry under vacuum for 24 hrs (0.426 g, 84.4% yield).
Reaction SMILES: C(O)C.Cl.[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[NH:7])[NH2:6].[O-]CC.[Na+].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=O)[CH2:33]Br)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[CH2:12]([O:11][C:9]([C:8]1[CH:33]=[C:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:27][CH:28]=2)[NH:7][C:5]=1[NH2:6])=[O:10])[CH3:13]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)[nH]c1N
Temperature: 25 °C
Yield: 103.1 %

Procedure:
After adding 700 ml of ethanol to 50.7 g of ethyl 2-amidinoacetate hydrochloride (a publicly known compound described in Liebigs Ann. Chem., 1895 (1977)), the mixture was stirred at room temperature, 22.3 g of sodium ethoxide (1 equivalent with respect to ethyl 2-amidinoacetate hydrochloride) was added, and the mixture was stirred for 15 minutes under a nitrogen atmosphere. To this there was added 49.9 g of 1-(4-benzyloxyphenyl)-2-bromoethanone (publicly known compound described in Journal of Heterocyclic Chemistry, vol. 2, 310 (1965) and Journal of Medicinal Chemistry, vol. 17, 55 (1974)), and the mixture was stirred for 36 hours at room temperature under a nitrogen atmosphere. Water was added, ethyl acetate was used for liquid separation and extraction, and then the organic layer was dried over sodium sulfate and concentrated to dryness to obtain 56.7 g of the title compound.
Reaction SMILES: CN(OC)[C:3](=[O:19])[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][CH:24]=1.COCCOC.CCOC(C)=O>CCOCC>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:3](=[O:19])[CH2:4][CH2:5][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)=[CH:25][CH:24]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 68.9 %

Procedure:
N-Methyl-N-methoxy-3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propionamide (550 mg, 1.83 mmol, from Step B) was dissolved in 10 mL dry ether and the solution was cooled to 0° C. A solution of 4-fluorophenyl magnesium bromide (2 mL, 1.0 M in THF, 2.01 mmol) was added dropwise. A solid mass formed upon addition and 1 mL 1,2-dimethoxyethane was added. The mixture was warmed to room temperature and stirred for 45 min then poured into 100 mL EtOAc/10 mL 1 M aqueous HCl. The layers were separated and the organic phase was washed with water, then sat'd NaCl, then dried over Na2SO4 and concentrated. Flash chromatography (25 grams silica, 5/1 hexane/EtOAc eluant) afforded 423 mg (69%) of the title compound. 1H NMR (300 MHz, CDCl3) δ1.0-1.20 (m, 2H), 1.45 (s, 9H), 1.65-1.75 (m 4H), 2.6-2.75 (m 2H), 2.9-3.0 (t, 2H), 4.03-4.08 (m, 2H), 7.1-7.19 (m, 2H), 7.95-8.04 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)[CH3:2].[H-].[Na+].[Cl:17][C:18]1[CH:40]=[CH:39][C:21]([C:22]([N:24]2[CH2:29][CH2:28][CH:27]([NH:30][C:31]3[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][N:32]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1.C(OCC)(C)=O.O>C1COCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:24]2[CH2:25][CH2:26][CH:27]([NH:30][C:31]3[N:32]=[CH:33][C:34](/[CH:35]=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:14])=[CH:37][CH:38]=3)[CH2:28][CH2:29]2)=[O:23])=[CH:39][CH:40]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccc(NC2CCN(C(=O)c3ccc(Cl)cc3)CC2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(NC2CCN(C(=O)c3ccc(Cl)cc3)CC2)nc1
Temperature: 15 °C
Yield: 75.2 %

Procedure:
A solution of diethylphosphonoacetic acid ethyl ester (274 mg) in THF (10 ml) was added dropwise to a mixture of 60% sodium hydride in oil (55 mg) in THF (10 mL) with stirring at 10-20° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at ambient temperature for 30 minutes. A solution of 6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}nicotinaldehyde (210 mg) in THF (10 ml) solution was added to the above mixture and resultant mixture was stirred at ambient temperature for 1.5 hour. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-3-(6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylate (190 mg)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][C:3]1=2.[C:32]1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH3:32][N:29]1[CH2:30][CH2:31][C:3]2[N:2]([CH3:1])[C:10]3[CH:9]=[C:8]([N:11]4[CH:16]=[CH:15][C:14]([C:17]5[CH:18]=[N:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=5)=[CH:13][C:12]4=[O:27])[CH:7]=[CH:6][C:5]=3[C:4]=2[CH2:28]1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)cc31)CNCC2
Agent: Cl
Product: CN1CCc2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)cc3n2C)C1
Yield: 29 %

Procedure:
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (77 mg, 0.18 mmol) was reacted according to the procedure of Example 47 and converted to the dihydrochloride to provide the title compound (27 mg, 29%) as a yellow solid: mp 295-300° C.; 1H NMR (500 MHz, CD3OD) δ 9.09 (d, J=1.7 Hz, 1H), 8.42 (dd, J=8.1, 2.0 Hz, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.85 (d, J=7.1 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.15 (dd, J=8.3, 1.8 Hz, 1H), 7.02 (d, J=1.8 Hz, 1H), 6.89 (dd, J=7.1, 2.0 Hz, 1H), 4.79-4.37 (br m, 2H), 3.90-3.60 (br m, 5H), 3.30 (br m, 2H), 3.14 (s, 3H); ESI MS m/z 439 [M+H]+; HPLC (Method B)>99% (AUC), tR=12.4 min.