Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15]C(=O)OC(C)(C)C)[C:12]([O:23]COC)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:27]>C1COCC1>[ClH:27].[NH2:15][C:13]1[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:10]=[CH:11][C:12]=1[OH:23]
Reactant: COCOc1cnc(OCc2ccccc2)cc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cc(OCc2ccccc2)ncc1O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (2-(benzyloxy)-5-(methoxymethoxy)pyridin-4-yl)carbamate (11.0 g) in THF (10 mL) and 6 M hydrochloric acid (30 mL) was stirred at 60° C. for 8 hr. The reaction mixture was cooled to 0° C., and the precipitate was collected by filtration, and washed with hexane. The obtained solid was dried under reduced pressure to give the title compound (5.87 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=O)[CH2:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:5]=1)[CH3:2]>CC(O)=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:11]([CH2:12][NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(NC(=O)CNc2ccccc2)c(NCC(C)C)c1
Solvent: CC(=O)O
Product: CCOc1ccc2nc(CNc3ccccc3)n(CC(C)C)c2c1
Yield: 105.4 %

Procedure:
A solution of 60 (3.0 g, 0.0088 mol) in AcOH (50 mL) was heated at 100° C. for 3 hr. The mixture was then concentrated in vacuo. To the residue was added EtOAc (100 mL) and 37% aqueous ammonia (15 mL). The organic phase was washed with saturated NaHCO3 (2×75 mL) and brine (75 mL), filtered through phase separation filter paper, and concentrated in vacuo to give 3.0 g of a red oil. The oil was chromatographed on 30 g of silica gel with 10 g of anhydrous sodium sulfate on top packed with hexanes. The column was eluted with 25 mL portions of 10% CH2Cl2 in hexanes for fractions 1-4, 10% EtOAc in hexanes for fractions 5-8, 15% EtOAc in hexanes for fractions 9-12, 20% EtOAc in hexanes for fractions 13-16, 25% EtOAc in hexanes for fractions 17-20, 30% EtOAc in hexanes for fractions 21-24 and 35% EtOAc in hexanes for fractions 25-28. The product was eluted in fractions 21-27 to give 0.7 g (25%) of compound #9 as a brown oil. HPLC analysis showed a purity of 96%. 1H NMR (300 MHz, CDCl3): δ 7.65 (d, 1H), 7.3 (m, 2H), 6.95-6.75 (m, 5H), 4.7 (brs, 1H), 4.5 (s, 2H), 4.1 (q, 2H), 3.95 (d, 2H), 2.3 (m, 1H), 1.5 (t, 3H), 1.0 (d, 6H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.Cl.[CH3:13]O>>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[Cl:11]
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(Br)cc1Cl

Procedure:
3.0 g of 4-bromo-2-chloro-benzoic acid (12.74 mmol) were dissolved in 60 ml methanol and treated with 0.6 ml of concentrated HCl. After 17 h at reflux the reaction mixture was concentrated in vacuo, diluted with DCM and washed with a saturated aqueous NaHCO3 solution and brine, dried with magnesium sulfate, filtered and concentrated in vacuo leading to 2.7 g (85%) of 4-bromo-2-chloro-benzoic acid methyl ester as a light yellow oil. MS (+cEI): 250.0 (M).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:21]2[S:20][CH2:19][C:18]=1N1CCOCC1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.C(O)(=O)C.[BH4-].[Na+]>C(O)C>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@H:21]2[S:20][CH2:19][CH:18]=1)=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(N3CCOCC3)CS[C@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(CCc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 0 °C

Procedure:
11.4 g (20 mmols) of 7β-benzylacetylamino-3-morpholino-3-cephem-4-carboxylic acid benzhydryl ester are dissolved in 50 ml of ethanol, 50 ml of methylene chloride and 50 ml of glacial acetic acid. The solution is cooled to 0° C. and then, with stirring and under nitrogen, 4.08 g (120 mmols) of sodium borohydride are added in 200 mg portions over 1 hour, with vigorous evolution of gas after each addition. When the addition is complete, the reaction mixture is cooled to room temperature and, after addition of a further 50 ml of glacial acetic acid, stirred for 36 hours at room temperature. The clear, almost colourless solution is concentrated in a rotary evaporator and the residue is partitioned between water and methylene chloride. The organic phase is washed again with two 50 ml portions of water and then concentrated in vacuo, affording crude 7β-benzylacetylamino-3-cephem-4-carboxylic acid benzhydryl ester as a foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:13](=O)[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.CN.[C:19]([BH3-])#[N:20].[Na+]>>[CH3:19][NH:20][CH:13]1[CH:12]2[CH2:15][CH2:16][N:9]([CH2:10][CH2:11]2)[CH:8]1[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C2CCN(CC2)C1Cc1cccnc1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Product: CNC1C2CCN(CC2)C1Cc1cccnc1

Procedure:
Another illustration of derivatization of saturated ketone intermediates is the reductive amination to give amines. Thus, 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one reacts with ammonium formate, zinc chloride and sodium cyanoborohydride to give 3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane as predominantly the cis diastereomer. Likewise, reaction of 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one with methylamine and sodium cyanoborohydride provides 3-(methylamino)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane. These amine derivatives can be used as a template for library formation by reacting them with a variety of acylating agents (e.g., acid chlorides, acid anhydrides, active esters, and carboxylic acids in the presence of coupling reagents) and isocyanates to produce 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanes with amide and urea substituents in the 3-position of the 1-azabicyclo[2.2.2]octane, both of which classes are compounds of the present invention. Commercially unavailable isocyanates can be prepared in situ from corresponding amines and triphosgene in the presence of triethylamine. Such derivatives can be produced as single enantiomers, using the single enantiomers of 3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane and 3-(methylamino)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane as starting materials. For instance, the (2R,3R)- and (2S,3S)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanes can be produced by resolution of the cis 3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane, for example, using diastereomeric amides. Thus, when the cis amine is reacted with a chiral acid such as (S)—N-(tert-butoxycarbonyl)proline using a suitable coupling agent such as diphenylchlorophosphate, a pair of diastereomeric amides, separable by reverse phase chromatography, is produced. The separated proline amides can then be deprotected, for example, by treatment with trifluoroacetic acid (to remove the tert-butoxycarbonyl protecting group) and then the proline can be cleaved from the desired amine, for example, using Edman degradation conditions (i.e., phenylisothiocyanate, followed by trifluoroacetic acid).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.S([O-])([O-])(=O)=O.[Mg+2]>[O-2].[Mn+2].ClCCl>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(CO)cc3)ccc21
Agent: [Mn+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C=O)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.3 g (4 mmol) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzenemethanol and 20 ml of dichloromethane are introduced into a round-bottomed flask and 3.4 g (39.2 mmol) of manganese oxide are added. The mixture is stirred at room temperature for eight hours. Magnesium sulphate is added to the reaction medium, the mixture is filtered and the filtrate is evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of ethyl acetate and heptane (10/90). After evaporation of the solvents, 930 mg (29.5%) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzaldehyde are collected in the form of a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](=[O:42])[C:39](O)=[O:40])=[CH:30]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][C:39](=[O:40])[C:38]([C:31]3[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[NH:29][CH:30]=3)=[O:42])[N:13]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN)cc1
Reactant: O=C(O)C(=O)c1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CNC(=O)C(=O)c2c[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (209 mg, 0.51 mmol) in dry N,N-dimethylformamide (4 ml) was added 3-indole-glyoxylic acid (141 mg, 0.74 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (152 mg, 0.76 mmol), and 1-hydroxy-benzotriazole (100 mg, 0.74 mmol). The mixture was stirred at room temperature for 16 hours, diluted with dichloromethane (100 ml) and washed with water (100 ml), brine (100 ml), dried (MgSO4), filtered, and concentrated in vacuo. The residue was subjected to flash chromatography using a mixture of ethyl acetate/hexanes (2:5) as eluent, which afforded 143 mg (40%) of 2-amino-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)=O.[N-:17]=[C:18]=[S:19].[K+]>O.Cl>[F:14][C:13]([F:16])([F:15])[O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[NH:17][C:18](=[S:19])[NH:2][CH:3]=2)=[CH:7][CH:8]=1
Reactant: NCC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: [N-]=C=S
Agent: Cl
Agent: [K+]
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2c[nH]c(=S)[nH]2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
490 mg (1.89 mmol, 1 eq) of 2-amino-1-(4-(trifluoromethoxy)phenyl)ethanone hydrochloride and 320 mg (8.62 mmol, 4.5 eq) of potassium isothiocyanate are dissolved in 5 ml of water in the presence of 1 ml of a 2M hydrochloric acid solution. The reaction mixture is stirred at 100° C. for 16 hours. 320 mg (8.62 mmol, 4.5 eq) of potassium isothiocyanate are added and the reaction mixture is stirred at 100° C. for 16 hours. The medium is filtered and then the solid is washed with water. 320 mg of 4-(4-(trifluoromethoxy)phenyl)-1,3-dihydroimidazole-2-thione are collected.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: Cc1ccccc1CC(=O)O
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1ccccc1C)C(=O)OCC(C)C

Procedure:
Following General Procedure I above and using 2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: Br[C:2]1[CH:42]=[CH:41][CH:40]=[CH:39][C:3]=1[CH2:4][N:5]([CH2:28][C:29]([C:31]1[C:36]([Cl:37])=[CH:35][N:34]=[CH:33][C:32]=1[Cl:38])=[O:30])[C:6]([C:8]1[CH:9]=[N:10][N:11]([C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:12]=1[C:13]([F:16])([F:15])[F:14])=[O:7].C[C:44]([N:46](C)C)=O>[C-]#N.[C-]#N.[Zn+2].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:44]([C:2]1[CH:42]=[CH:41][CH:40]=[CH:39][C:3]=1[CH2:4][N:5]([CH2:28][C:29]([C:31]1[C:36]([Cl:37])=[CH:35][N:34]=[CH:33][C:32]=1[Cl:38])=[O:30])[C:6]([C:8]1[CH:9]=[N:10][N:11]([C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:12]=1[C:13]([F:16])([F:15])[F:14])=[O:7])#[N:46]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)cncc3Cl)Cc3ccccc3Br)c2C(F)(F)F)CC1
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)cncc3Cl)Cc3ccccc3C#N)c2C(F)(F)F)CC1
Temperature: 100 °C

Procedure:
A mixture of compound 22-3 (100 mg, 0.14 mmol) and Zn(CN)2 (34 mg, 0.28 mmol) in DMA (8 mL) was purged with argon for 10 min. Pd(PPh3)4 (33.4 mg, 0.02 mmol) was added and the mixture was heated at 100° C. for 3 h. The reaction mixture was cooled to room temperature, quenched with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 30% EtOAc/hexane) to provide compound 22-4 (27 mg, 29%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)#[N:18]>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:17]#[N:18])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: N#Cc1ccc(S(=O)(=O)Nc2cncc(-c3ccc(C#N)c(Cl)c3)c2)cc1
Yield: 39.4 %

Procedure:
According to General Sulfonylation Procedure 2 in example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, 1 eq) in anhydrous pyridine (500 μl) was added 4-cyano-benzenesulfonyl chloride (19.3 mg, 96 μmol, 1.1 eq). The product was purified by preparative TLC, the plate was eluted with dichloromethane/methanol 95/5, to give (15.5 mg, >95% purity, yield: 39.4%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:33][CH2:32][CH2:31][N:30]([CH3:34])[CH3:29])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Reactant: CN(C)CCN
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)NCCN(C)C)cc3C)cc12

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-N-(2-(dimethylamino)ethyl)-3-methylbenzamide was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and N1,N1-dimethylethane-1,2-diamine following the procedures described for Example 117. 1H NMR (methanol-d4): δ 8.60 (s, 1H), 8.39 (s, 1H), 8.08 (d, 1H), 7.68 (s, 1H), 7.57-7.59 (m, 2H), 7.19-7.22 (m, 2H), 3.57-3.61 (m, 2H), 3.07-3.16 (m, 4H), 2.64-2.67 (m, 2H), 2.52 (s, 3H), 2.38 (s, 6H), 2.35 (s, 3H). LRMS [M+H]=442.3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:10][C:11]([NH:14][NH:15][C:16](=O)[CH2:17][C:18]2[C:19]([CH3:28])=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)=[N:12][CH:13]=1.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:10][C:11]2[N:12]([C:16]([CH2:17][C:18]3[C:19]([CH3:28])=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)=[N:15][N:14]=2)[CH:13]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CC(=O)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cn12
Temperature: 180 °C

Procedure:
A solution of N′-(5-(2-chlorophenyl)-4-(4-chlorophenyl)pyridin-2-yl)-2-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acetohydrazide (80 mg, 0.15 mmol) and acetic acid (0.5 mL) in ethanol (1 mL) was heated in a microwave oven at 180° C. for 30 min. Analysis by HPLC/MS indicated about 40% of starting material remained. The reaction mixture was heated again in a microwave oven at 180° C. for additional 30 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was taken into EtOAc, and the solution was washed with saturated aqueous NaHCO3, saturated aqueous NaCl dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 70% to 100% B, 10 min gradient, 100% B hold for 4 min, (A=90% H2O, 10% MeOH and B=10% H2O, 90% MeOH); Flow rate at 20 mL/min, UV detection at 220 nm) to yield the desired product with about 64% purity. The product was further purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-70%) in hexanes to afford 18 mg (23%) of the title compound. HPLC/MS (method A): retention time=3.91 min, (M+H)+=513.1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8](OCC)=O)=[CH:5][C:6]=1[CH3:7].[CH2:13]=O.O.N>C(O)(=O)C.I.[PH2](O)=O>[CH3:8][C:4]1[NH:3][C:2]([CH3:1])=[C:6]([CH3:7])[C:5]=1[CH3:13]
Reactant: C=O
Reactant: CCOC(=O)c1cc(C)c(C)[nH]1
Agent: I
Agent: N
Agent: O=[PH2]O
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]c(C)c(C)c1C
Yield: 53 %

Procedure:
A solution of 2,3-dimethyl-5-carbethoxy-pyrrole (0.82 g) in acetic acid (10 ml), hydriodic acid (10 ml), hypophosphorous acid (2 ml) and paraformaldehyde (0.6 g) was stirred and heated at 100° under nitrogen for 3 hr. then poured into water. The mixture was made alkaline with ammonia and extracted with ether. The ether was evaporated and the residue distilled (65°, 15 mm) to give the product (53%) m.p. 105°-107°.
Reaction SMILES: [CH3:1][NH2:2].[ClH:3].[Cl:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][N:7]=1>[Pd].CO>[ClH:4].[ClH:3].[CH3:1][NH:2][CH2:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@@H:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][NH:7]1
Reactant: ClCC1=NCC(c2ccccc2)c2ccccc21
Reactant: CN
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC[C@@H]1NC[C@H](c2ccccc2)c2ccccc21

Procedure:
To a stirred solution of methanol (1 liter) and monomethylamine (300 ml) maintained under nitrogen and cooled in an ice bath was added portionwise 1-chloromethyl-3,4-dihydro-4-phenylisoquinoline hydrochloride (83.0 g, 0.28 m) and the mixture heated to reflux (ca 50°-55°) for 2 hours. After cooling, the solution was poured into a pressure bottle and hydrogenated on a Parr apparatus over 5% Pd/C catalyst (5.0 g) at 40 psi for 16 hours. The catalyst was removed by filtration and the solvent evaporated to a gummy residue. This was dissolved in a mixture of methanol (200 ml) and isopropanol (200 ml) and acidified with HCl gas. Upon cooling and standing, a white solid crystallized which was collected by filtration and dried to give 64.0 g of the major isomer cis-1,2,3,4-tetrahydro-1-methylaminomethyl-4-phenyl-isoquinoline dihydrochloride, m.p. 276°-277°. A second crop of solid was obtained from the crystallization (26.1 g) which consisted (TLC) mostly of the minor isomer. Two recrystallizations of this crop provide the pure minor isomer trans-1,2,3,4-tetrahydro-1-methylaminomethyl-4-phenylisoquinoline, m.p. 269°-270°.
Reaction SMILES: [OH-].[Na+].[CH3:3]I.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][N:7]=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].O.C(Cl)Cl>[CH3:3][N:7]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]1=[O:5]
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(O)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cn1cc([N+](=O)[O-])ccc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tetra-N-butylammonium bromide (3220 mg, 10.00 mmol), sodium hydroxide (400.0 mg, 10.00 mmol) and methyl iodide (3113 μL, 50.00 mmol) were sequentially added into the two-phase mixture of 2-hydroxy-5-nitropyridine (700.0 mg, 5.000 mmol) in water (25 mL) and methylene chloride (50 mL). The above mixture was stirred at rt for 1 h and then partitioned between CH2Cl2 (50 mL) and water (75 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo to obtain a beige solid. Silica gel (134 g) was used to purify the above solid eluting with 2500 mL EtOAc to obtain the title compound as beige powder. 1H NMR (CDCl3, 400 MHz): δ=3.66 (s, 3H), 6.57 (d, 1H, J=10.0 Hz), 8.10 (dd, 1H, J=2.8 & 10.0 Hz), 8.63 (d, 1H, J=2.8 Hz). MS (ES+): m/z 155.15 (100) [MH+]. HPLC: tR'1.69 min (ZQ2000, polar—5 min).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[OH:8][C:9]1[CH:14]=[CH:13]C(O)=[C:11](C)[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:5]([O:4][C:1]1[CH:11]=[CH:10][C:9]([OH:8])=[C:14]([CH3:13])[CH:2]=1)(=[O:7])[CH3:6]
Reactant: Cc1cc(O)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(=O)Oc1ccc(O)c(C)c1
Reaction time: 8 h
Yield: 3.1 %

Procedure:
Acetic anhydride (4.73 gm, 4.37 mL, 46.3 mMol) was added dropwise to a mixture of 4-hydroxy-2-methylphenol (5 gm, 46.3 mMol) and cesium carbonate (15.1 gm, 46.3 mMol) in acetonitrile (50 mL). After stirring overnight, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 5:1 pentane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.24 gm (3%) of the desired compound.