Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[CH3:29][C:30]1[C:35]([C:36](O)=[O:37])=[CH:34][N:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]([CH:25]([CH3:26])[CH3:27])[C:36](=[O:37])[C:35]3[C:30]([CH3:29])=[CH:31][CH:32]=[N:33][CH:34]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28]
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Reactant: Cc1ccncc1C(=O)O
Product: Cc1ccncc1C(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(C)C

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with 4-methyl-nicotinic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 516. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.3 (s, 1H)) 8.6 (s, 1H) 8.5 (s, 1H) 8.3 (d, 1H) 8.1 (s, 1H) 7.9 (d, 1H) 7.5 (m, 1H) 7.4 (m, 2H) 7.2 (m, 3H) 6.9 (d, 1H) 5.6 (s, br, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.0 (d, 1H) 2.9 (m, 2H) 2.7 (s, 3H) 1.2 (d, 6H).
Reaction SMILES: N.[NH2-].[Na+].[C:4]1([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:18][CH:19]=[CH2:20].[Cl-].[NH4+]>O.C(OCC)C>[C:4]1([CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:20][CH:19]=[CH2:18])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: C=CCBr
Agent: N
Agent: [Cl-]
Agent: [NH2-]
Solvent: CCOCC
Solvent: O
Product: C=CCC(c1ccccc1)c1ccccc1
Reaction time: 0.75 h

Procedure:
A solution of 1.5 1. of liquid ammonia containing 19.5 g. of sodium amide was stirred while a solution of 84.1 g. of diphenylmethane dissolved in 200 ml. of diethyl ether was added dropwise over about 30 minutes. The reaction mixture was stirred for 45 minutes after the addition was completed. A solution of 60.5 g. of 3-bromo-1-propene in 50 ml. of diethyl ether was then added to the reaction mixture, after which time the mixture was stirred for twelve hours. A saturated aqueous solution of ammonium chloride was then added to the reaction mixture, followed by the addition of 500 ml. of water. The product was extracted from the aqueous reaction mixture into diethyl ether. The ethereal extracts were combined, washed, and dried. Evaporation of the solvent under reduced pressure provided 93.2 g. of the product as an oil. Distillation of the crude oil afforded 4,4-diphenyl-1-butene, B.P. 95°-98° C 0.10 torr.
Reaction SMILES: Cl.Cl.Cl.Cl.[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([N:18]3[CH:27]([CH3:28])[CH2:26][C:25]4[C:20](=[CH:21][C:22]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:23][CH:24]=4)[CH2:19]3)[N:15]=[C:14]([NH2:35])[N:13]=2)[CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.[CH3:45][N:46]([CH3:50])[C:47](Cl)=[O:48]>C(#N)C.CO>[NH2:35][C:14]1[N:15]=[C:16]([N:18]2[CH:27]([CH3:28])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH:29]4[CH2:30][CH2:31][N:32]([C:47]([N:46]([CH3:50])[CH3:45])=[O:48])[CH2:33][CH2:34]4)=[CH:23][CH:24]=3)[CH2:19]2)[CH:17]=[C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH3:5])[CH2:7][CH2:8]2)[N:13]=1
Reactant: CN(C)C(=O)Cl
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Solvent: CO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1Cc2ccc(C3CCN(C(=O)N(C)C)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-Methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine tetrahydrochloride (17 mg) HCl salt in acetonitrile (0.50 mL) was treated with N,N-diisopropylethylamine (42 uL, 0.24 mmol). To the solution was added N,N-Dimethylcarbamoyl chloride (3.59 uL, 0.0390 mmol). The mixture was stirred at r.t. for 2 h. The mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS:(M+H)+=493.4.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(=O)Oc1ccc(CCl)cc1
Solvent: O
Product: CC(=O)Oc1ccc(CN2CCOCC2)cc1
Temperature: 70 °C

Procedure:
To 4-(chloromethyl)phenyl acetate (2.5 g, 13.5 mmol) was added neat morpholine (3.0 mL, 34.4 mmol) at r.t. The solution was heated to 70° C. for 45 min, then cooled. Water (10 mL) was added and the solution was extracted with 10% methanol in dichloromethane (4×20 mL). The combined organics were washed with brine, dried with Na2SO4, and concentrated. Purification on silica gel (10% methanol/dichloromethane) gave the title compound.
Reaction SMILES: C([N:3](CC)CC)C.[CH3:8][O:9][C:10]1[N:15]=[C:14]2[NH:16][C:17]3[C:22]([C:23](O)=[O:24])=[CH:21][C:20]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[N:19][C:18]=3[C:13]2=[CH:12][CH:11]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Cl-].[NH4+]>CN(C)C=O>[CH3:8][O:9][C:10]1[N:15]=[C:14]2[NH:16][C:17]3[C:22]([C:23]([NH2:3])=[O:24])=[CH:21][C:20]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[N:19][C:18]=3[C:13]2=[CH:12][CH:11]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(-c2cc(C(=O)O)c3[nH]c4nc(OC)ccc4c3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4nc(OC)ccc4c3n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
Dimethylformamide (0.6 mL) followed by triethylamine (47 μL, 0.34 mmol) were added to a mixture of 7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[2′,3′:4,5]pyrrolo[2,3-b]pyridine-4-carboxylic acid (74 mg, 0.21 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodimide hydrochloride (53 mg, 0.28 mmol), 1-hydroxybenzotriazole hydrate (42 mg, 0.28 mmol), and ammonium chloride (18 mg, 0.34 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent were removed under vacuum and the residue was suspended in about 10 mL of dimethylsulfoxide. The solid was collected by filtration and washed with a little dimethylsulfoxide and water. This was dried under vacuum over solid sodium hydroxide to leave 7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[2′,3′:4,5]pyrrolo[2,3-b]pyridine-4-carboxamide (51 mg, 66% yield) as a yellow solid. MS (ESI) m/z 349.2 (M+H). 1H NMR (DMSO-d6) δ ppm 11.36 (1H, br. s.), 8.49 (2H, d, J=8.06 Hz), 8.26 (1H, s), 8.20 (2H, d, J=8.56 Hz), 7.86 (1H, br. s.), 7.09 (2H, d, J=8.56 Hz), 6.75 (1H, d, J=8.31 Hz), 4.00 (3H, s), 3.84 (3H, s).
Reaction SMILES: C(OC(Cl)=O)C.[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.C(N(CC)CC)C.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CC(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:14])=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: NCCN1CCOCC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.3 Ml. of chloroformic acid ethyl ester are added dropwise to a solution of 8.6 g. of p-chlorobenzoic acid and 7.6 ml. of triethylamine in 150 ml. of acetone, with stirring and cooling with ice-water. After one hour at 0° C., a solution of 6.5 g. of N-(2-aminoethyl)-morpholine in 50 ml. of acetone is added dropwise to the mixture and the mixture is then stirred overnight at room temperature. Thereafter it is concentrated, allowed to stand for 2 hours in the refrigerator and filtered. The filtrate is evaporated to dryness and the residue is taken up in 250 ml. of water and 250 ml. of methylene chloride. The phases are separated and the methylene chloride extract is dried over sodium sulfate and evaporated. The residue is recrystallized from isopropanol and 7.8 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: O[CH2:2][CH2:3][S:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].CS(Cl)(=O)=O.[Br-:21].[Li+]>>[Br:21][CH2:2][CH2:3][S:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C)(C)CCCSCCO
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Product: CCOC(=O)C(C)(C)CCCSCCBr
Yield: 62 %

Procedure:
from ethyl 8-hydroxy-2,2-dimethyl-6-thiaoctanoate and methanesulphonyl chloride and subsequent reaction of the resultant methanesulphonyloxy compound with lithium bromide. Yield 62% of theory; colourless oil;
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[CH2:20][CH2:21][O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)=[CH:26][C:24]=3[CH:25]=2)=[O:18])=[CH:12][CH:11]=1)=[O:9].B.[Na].O>CO>[OH:9][CH:8]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:2]1[CH3:1])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[CH2:20][CH2:21][O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=4)=[CH:26][C:24]=3[CH:25]=2)=[O:18])=[CH:12][CH:11]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=O)C4CCCCN4C)cc2)CCO3)cc1
Agent: B
Agent: [Na]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)C4CCCCN4C)cc2)CCO3)cc1
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
In methanol (40 ml) was dissolved N-(4-(1-methylpiperidin-2-ylcarbonyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.1 g) under ice-cooling, and to the mixture was added sodium boron hydride (10 mg). The mixture was stirred for 15 minutes, and to the mixture was added water. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol-ethyl acetate-hexane to give N-(4-(hydroxy(1-methylpiperidin-2-yl)methyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 158) (0.07 g) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[NH2:13][C:14]1[CH:19]=[C:18](Cl)[C:17]([C:21]#[N:22])=[CH:16][N:15]=1>CS(C)=O>[NH2:13][C:14]1[CH:19]=[C:18]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[C:17]([C:21]#[N:22])=[CH:16][N:15]=1
Reactant: N#Cc1cnc(N)cc1Cl
Reactant: Oc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1cnc(N)cc1Oc1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 19.4 %

Procedure:
5-Hydroxyindole (313 mg, 2.35 mmol) was dissolved in dimethyl sulfoxide (3 ml); and sodium hydride (90 mg, 2.25 mmol) was gradually added thereto while stirring at room temperature. After the reaction mixture was stirred for 1 hour, 2-amino-4-chloro-5-cyanopyridine (300 mg, 1.96 mmol) synthesized in Production example 215-3 was added thereto; and the reaction mixture was heated and stirred at 120° C. for 4 hours. After allowing to be cooled to room temperature, the reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off; the residue was subjected to silica gel column chromatography (Fuji Silysia NH, ethyl acetate-methanol); fractions containing the desired compound was concentrated under reduced pressure; ether was added thereto; and the solid was filtered off, and dried under reduced pressure to yield the title compound (95 mg, 0.38 mmol, 59%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:30]=O)[C:24]=2[CH:23]=[CH:22][N:21]=1>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[C:29]5[C:24]=4[CH:23]=[CH:22][N:21]=[CH:20]5)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: O=Cc1cccc2cnccc12
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccc5cnccc45)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with isoquinoline-5-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 5-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]isoquinoline.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](O)(=[O:13])[CH:10]([CH3:12])[CH3:11].B(F)(F)F>CC([O-])=O.[Na+]>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:9](=[O:13])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)C(=O)O
Reactant: Oc1cccc(O)c1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Product: CC(C)C(=O)c1ccc(O)cc1O
Yield: 113.1 %

Procedure:
Resorcinol (10.0 g, 91 mmol) and isobutyric acid (8.00 g, 1 eq.) were treated with BF3-etherate (68 mL, 6 eq.) and heated for 1.5 h to 90° C. After cooling the reaction mixture was carefully poured onto 500 mL of 10% aq. NaOAc solution, twofold extracted with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness to leave 18.5 g of the title compound as light brown oil.
Reaction SMILES: [C:1]([NH:5][N:6]=[C:7]([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:17]Br>CCCCC>[C:1]([N:5]=[N:6][C:7]([Br:17])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=NNC(C)(C)C
Reactant: BrBr
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)N=NC(C)(C)Br
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Into a solution of 25.6 grams (0.2 mole) of acetone t-butylhydrazone and 20.3 grams (0.2 mole) of triethylamine in 200 ml of pentane, cooled to 5° C in a 500 ml 4-neck round bottom flask equipped with a mechanical stirrer and thermometer, was added 31.9 grams (0.2 mole) of bromine from an addition funnel. After the addition was complete the reaction was stirred an additional 1/2 hour at 5° C, filtered to remove the triethylamine hydrobromide and the pentane evaporated from the filtrate under reduced pressure. The residue was an orange yellow liquid weighing 40 grams (96.6% crude yield). The infrared spectrum of the residue was in agreement with the structure of 2-t-butylazo-2-bromopropane.
Reaction SMILES: [NH2:1][C:2]1([CH2:31][CH2:32][CH2:33][CH3:34])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:16]=3[S:15](=[O:29])(=[O:28])[N:14]=2)[C:3]1=[O:30].C(N(CC)CC)C.[C:42](OC(=O)C)(=[O:44])[CH3:43].C([O-])([O-])=O.[K+].[K+]>ClCCl.CO.O>[CH2:31]([C:2]1([NH:1][C:42](=[O:44])[CH3:43])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:16]=3[S:15](=[O:29])(=[O:28])[N:14]=2)[C:3]1=[O:30])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCC1(N)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCC1(NC(C)=O)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 26 (20 mg, 0.04 mmol) in dichloromethane (0.5 mL) was added triethylamine (17 μL, 0.12 mmol) and acetic anhydride (7 μL, 0.08 mmol) and the solution was stirred at room temperature for 16 hours. Solvent was removed in vacuo to yield bis-substituted material which is dissolved in methanol (2 mL) and solid K2CO3 (excess) was added and the solution stirred at room temperature for 1 hour. H2O (5 mL) was added and the solution extracted with ethyl acetate (3×5 mL). The combined extracts were washed with brine (1×5 mL), dried (Na2SO4), the drying agent filtered and the solvent removed in vacuo to give a crude residue which was purified by column chromatography on silica gel (3% methanol/chloroform) to give the title compound as a colorless solid. 1H NMR (d6-DMSO) δ 10.00 (s, 1H), 8.04, 8.01 (d, 1H), 7.57-7.33 (m, 6H), 3.02 (s, 3H), 1.91-1.79 (m, 1H), 1.82 (s, 3H), 1.72-1.62 (m, 1H), 1.31-1.13 (m, 2H), 0.89-0.63 (m, 2H), 0.72-0.63 (m, 3H). MS (ESI) m/z 547 (M+H+).
Reaction SMILES: [OH-].[K+].Cl.Cl.[NH2:5][CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1.[Cl-].[Na+].[Cl:16][CH2:17][C:18](Cl)=[O:19]>O.C(Cl)Cl>[ClH:16].[N:8]12[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9]1)[CH:6]([NH:5][C:18](=[O:19])[CH2:17][Cl:16])[CH2:7]2
Reactant: O=C(Cl)CCl
Reactant: NC1CN2CCC1CC2
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)NC1CN2CCC1CC2
Reaction time: 0.5 h
Yield: 144 %

Procedure:
Potassium hydroxide (10 g) was added to a solution of 3-aminoquinuclidine dihydrochloride (10.45 g, 0.052 mole) in water (80 ml) saturated with sodium chloride. After stirring for 30 minutes, methylene chloride (75 ml) was added and the layers separated. The aqueous layer was washed with methylene chloride (2×75 ml), and the extracts combined with the methylene chloride layer above; dried over sodium sulfate, filtered, and the volume reduced to 100 ml. A solution of chloroacetyl chloride (3.11 g, 0.0273 mole) in methylene chloride (25 ml) was added dropwise and the mixture stirred overnight. The solvent was removed on a rotary evaporator. The residue was recrystallized from methanol-ethyl acetate to give a white solid (4.7 g), m.p. ca. 189°-195° C. The structure was confirmed by NMR.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[NH2:6].[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:20]=1[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[NH:6][C:21]([C:20]1[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:19]=1[Cl:18])=[O:22]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.2 %

Procedure:
To a solution of 4-nitro-L-phenylalanine methyl ester hydrochloride salt (7.44 mmol, 1.94 g), 2chloro-6-methylbenzoic acid (8.2 mmol, 1.4 g) and HBTU (8.2 mmol, 3.11 g) in DMF (27 mL) was added diisopropylethylamine (18.6 mmol, 3.24 mL) at room temperature. The clear solution was stirred for 48 h at room temperature and was diluted with 100 mL of ethyl acetate. The solution was washed in turn with 0.5N hydrochloric acid (2×50 mL), saturated sodium bicarbonate solution (2×50 mL), brine (100 mL) then was dried (MgSO4) and filtered. Concentration of the solution to dryness gave 2.67 g (95%) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-nitro-L-phenylalanine methyl ester as a colorless solid, mp 120-123° C. HRMS: Obs. mass, 376.4274. Calcd. mass, 376.4238 (M+H).
Reaction SMILES: [CH:1]1[CH:13]=[CH:12][C:11]2[C:14](=[O:17])[CH2:15][CH2:16][N:9]3[C:10]=2[C:2]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=13.C([Li])CCC.[CH:23](=[O:26])[CH2:24][CH3:25].[Cl-].[NH4+]>O1CCCC1>[OH:26][CH:23]([C:15]1[C:14](=[O:17])[C:11]2[CH:12]=[CH:13][CH:1]=[C:2]3[C:10]=2[N:9]([CH:16]=1)[C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]3=1)[CH2:24][CH3:25]
Reactant: CCC=O
Reactant: O=C1CCn2c3ccccc3c3cccc1c32
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1cn2c3ccccc3c3cccc(c1=O)c32
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5,6-dihydro-4H-pyrido[3,2,1-jk]carbazole-4-one (800 mg) prepared by the procedure described in J.O.C., 24, 324 (1959) was dissolved in anhydrous tetrahydrofuran (30 ml). n-butyl lithium (solution in hexane, 3 ml) was added dropwise to the solution cooled in an acetone-dry ice bath, and the mixture was stirred for 30 minutes. Propionaldehyde (0.29 ml) dissolved in anhydrous tetrahydrofuran (15 ml) was gradually added dropwise to the solution cooled in an acetone-dry ice bath, and the mixture was stirred for 90 minutes. Saturated aqueous solution of ammonium chloride of an adequate amount was added to the reaction mixture, and the mixture was heated to room temperature, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=4:1) to obtain the title compound as a diastereomer (450 mg, 45%).
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].CO[C:16]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=1[NH2:18]>C(O)CO>[CH3:24][O:23][C:21]1[CH:22]=[CH:16][C:17]([NH:18][C:2]2[N:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])=[CH:19][CH:20]=1
Reactant: C#CCNC(=O)c1cccnc1Cl
Reactant: COc1ccc(N)c(OC)c1
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1ccc(OC)cc1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-methoxyaniline (9e, 123 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10e as pure product. To a solution of 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10e, 150 mg, 0.53 mmol) and 1-(azidomethyl)-3,5-dimethoxybenzene (12d, 102 mg, 0.58 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 6e (197 mg, 78%); mp: 147-149° C.; 1H NMR (300 MHz, CDCl3) δ 10.17 (s, 1H), 8.24 (dd, J=4.9, 1.7 Hz, 1H), 7.55-7.48 (dd, J=7.7, 1.7 Hz, 1H), 7.17 (t, J=5.0 Hz, 1H), 6.87 (d, J=8.8 Hz, 2H), 6.62-6.57 (m, 1H), 6.42-6.39 (m, 3H), 5.42 (s, 2H), 4.66 (d, J=5.4 Hz, 2H), 3.79 (s, 3H), 3.75 ppm (s, 6H) MS (ESI m/z): 475 [M+H]+. Yield: 78%
Reaction SMILES: Cl.[CH:2]([N:5]([CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:6](=[O:8])[CH3:7])([CH3:4])[CH3:3].F[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:20]([C:19]1[CH:22]=[CH:23][C:16]([N:12]2[CH2:11][CH2:10][CH:9]([N:5]([CH:2]([CH3:4])[CH3:3])[C:6](=[O:8])[CH3:7])[CH2:14][CH2:13]2)=[CH:17][CH:18]=1)=[O:21]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)N(C(C)C)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C(C)C)C1CCN(c2ccc(C=O)cc2)CC1
Temperature: 120 °C
Yield: 71.3 %

Procedure:
To a solution of N-isopropyl-N-(piperidin-4-yl)acetamide hydrogen chloride (0.260 g, 1.41 mmol) in DMF (5 mL) was added 4-fluorobenzaldehyde (0.18 mL, 1.69 mmol) and K2CO3 (0.233 g, 1.69 mmol). The resulting solution was heated to 120° C. overnight, and cooled. The cooled solution was diluted with water and extracted with CH2Cl2. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 0% to 5% MeOH/CH2Cl2, to afford N-(1-(4-formylphenyl)piperidin-4-yl)-N-isopropylacetamide (0.290 g, 71%).