Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]#[N:13])[CH2:7][CH2:6][CH2:5]2.[CH2:15](N)[CH2:16][NH2:17]>>[ClH:14].[NH2:1][C:2]1[C:3]([Cl:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[NH:17][CH2:16][CH2:15][N:13]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: N#CC1CCCc2c1ccc(N)c2Cl
Reactant: NCCN
Product: Cl
Product: Nc1ccc2c(c1Cl)CCCC2C1=NCCN1
Yield: 60 %

Procedure:
Utilizing the procedure of Example 74 with 6-amino-1-cyano-5-chloro-(1,2,3,4-tetrahydronaphthalene) (1.2 g) and ethylenediamine (3 ml) gave the desired compound in 60% yield. m.p. 220° C. (decomp.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](S(C)(=O)=O)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[S:26]1(=[O:33])(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][S:26]2(=[O:33])=[O:32])[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:5])[CH3:2]
Reactant: O=S1(=O)CCCCN1
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(N2CCCCS2(=O)=O)n(C)c(=O)c1OCc1ccccc1
Yield: 92.5 %

Procedure:
Reaction of 2-methanesulfonyl-5-benzyloxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (2.21 g, 6.03 mmol) and [1,2]thiazinane 1,1-dioxide (0.97 g, 7.2 mmol) in dry N,N-dimethylformamide (30 ml) with sodium hydride (0.35 g of a 60% dispersion in mineral oil, 8.8 mmol) gave 2.35 g (92% yield) of the title ester as white needles; mp 109–110° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.29 (3H, t, J=7.1 Hz, CH3), 1.62 (1H, m, CH), 2.3–2.6 (3H, m, CH2 and CH), 3.15–3.21 (1H, m, CH), 3.5–3.6 (1H, m, CH), 3.64 (3H, s, NCH3), 3.64 (1H, m overlapping with NCH3, CH), 3.97–4.05 (1H, m, CH), 4.32 (2H, q, J=7.1 Hz, OCH2), 5.29 (2H, AB system, JAB=10.6 Hz, Δν=62.5 Hz, OCH2), 7.3–7.5 (5H, m, aromatics). Anal. Calcd for C19H23N3O6S: C 54.15, H 5.50, N 9.97. Found: C 53.88, H 5.40, N 9.91.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]1[S:16](=O)[CH2:15][CH2:14][CH2:13]1.[ClH:18]>CO>[Cl-:18].[OH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S+:16]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:3][CH:2]=1
Reactant: Cl
Reactant: Oc1cccc2ccccc12
Reactant: O=S1CCCC1
Solvent: CO
Product: Oc1ccc([S+]2CCCC2)c2ccccc12
Product: [Cl-]
Temperature: -16 °C

Procedure:
In 50 g of methanol were dissolved 10 g (0.069 mol) of 1-naphthol and 7.2 g (0.069 mol) of tetramethylene sulfoxide. The solution was cooled to −16° C. An excess of hydrogen chloride gas was fed to the solution at a temperature below 20° C. Nitrogen gas was bubbled to expel the excess of hydrogen chloride. The reaction solution was concentrated and combined with water and diisopropyl ether, from which a water layer was separated. It was an aqueous solution of 4-hydroxynaphthyl-1-tetrahydrothiophenium chloride. This aqueous solution was used in the subsequent step without further isolation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C:15]([C:25](=O)[CH3:26])=[CH:16][C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([CH2:31][CH2:32][O:33][C:34](=[O:39])/[CH:35]=[C:36](\[NH2:38])/[CH3:37])#[N:30]>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:15]2[CH:16]([C:17]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=3)[C:35]([C:34]([O:33][CH2:32][CH2:31][C:29]#[N:30])=[O:39])=[C:36]([CH3:37])[NH:38][C:25]=2[CH3:26])=[O:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C/C(N)=C/C(=O)OCCC#N
Reactant: CC(=O)C(=Cc1cc(Cl)cc(Cl)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CC(C)O
Product: CC1=C(C(=O)OCCC#N)C(c2cc(Cl)cc(Cl)c2)C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)=C(C)N1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
1.66 g (3.88 mmol) of 4-[2-acetyl-3-(3,5-dichlorophenyl)-2-propenoyl] piperazine-1-carboxylic acid t-butyl ester and 598 mg (3.88 mmol) of 3-aminocrotonate 2-cyanoethyl ester were stirred in 30 ml of 2-propanol at 80° C. overnight and then stirred at 120° C. for 2 hours. After concentration under reduced pressure, ethyl acetate was added and the residue was washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol =100/1 to 30/1) to obtain the title compound.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]([C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1)=[O:8].Br[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>O.COCCOC.ClCCl.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>[N:20]1[CH:21]=[CH:22][CH:23]=[N:24][C:19]=1[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH:7]=[O:8]
Reactant: Brc1ncccn1
Reactant: O=Cc1cccc(B(O)O)c1
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: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: O=Cc1cccc(-c2ncccn2)c1
Yield: 63.3 %

Procedure:
A mixture of Na2CO3 (4.74 g, 44.72 mmol) and 3-formylphenylboronic acid (3.40 g, 22.67 mmol) in water (15 mL) were added to a solution of 2-bromopyrimidine (3.00 g, 18.87 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.72 g, 0.62 mmol) in DME (30 mL) and the mixture was heated to reflux for 24 h. The cooled reaction mixture was diluted with dichloromethane, washed with sat. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 1:1 hexane/ethyl acetate) yielded 2.20 g (63%) of the title compound. MS 185 (M+H)+.
Reaction SMILES: C(O[CH:4]([O:13]CC)[C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)C.[NH2:16]O.O.[C:19](Cl)(=[O:21])[CH3:20]>C(O)C>[CH3:20][C:19]1[O:21][N:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH:4]=[O:13])=[CH:10][N:9]=2)[N:16]=1
Reactant: CCOC(OCC)c1ccc(C#N)nc1
Reactant: NO
Reactant: CC(=O)Cl
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccc(C=O)cn2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
In ethanol (5 mL) was dissolved 5-(diethoxymethyl)picolinonitrile (230 mg, 1.12 mmol) obtained in Step 1. A 50% aqueous hydroxylamine solution (0.368 g, 5.58 mmol) was added and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The resulting white solid was dissolved in pyridine (5 mL). Acetyl chloride (0.396 mL, 5.58 mmol) was added and the mixture was stirred at 100° C. for 12 hours. The solvent in the reaction mixture was evaporated under reduced pressure and water was added. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/7) to give 6-(5-methyl-1,2,4-oxadiazol-3-yl)nicotinaldehyde (200 mg, 95% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([I:8])=[CH:4][N:3]=1.[C:9](=O)([O-])[O-].[Cs+].[Cs+].C[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CN(C=O)C>[I:8][C:5]1[N:6]=[CH:7][C:2]([N:16]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:9])[CH2:17]2)=[N:3][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1cnc(I)cn1
Reactant: CN1CCNCC1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1CN(c2cnc(I)cn2)CCN1
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A mixture of 2-bromo-5-iodopyrazine (200 mg, 0.704 mmol), cesium carbonate (400 mg, 1.23 mmol) and 2R methyl piperazine (85 mg, 0.85 mmol) in DMF (10 ml) was stirred at 100° C. overnight. The reaction was cooled and solvent evaporated. Water (100 ml) was added and insoluble solid was filtered, then dissolved in MeCl2 (100 ml), dried over Na2SO4, filtered and solvent evaporated yielding product (205 mg, 95%) Mass Spec (MH, 305)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][CH:7]=[N:6][C:5]2=[O:14].CO.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:24][CH3:25]>O.CC#N>[CH2:24]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][CH:7]=[N:6][C:5]2=[O:14])[CH3:25]
Reactant: CCI
Reactant: COc1cc2[nH]cnc(=O)c2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CCOc1cc2c(=O)nc[nH]c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
A mixture of 6-hydroxy-7-(methyloxy)-4(1H)-quinazolinone (1 g, 5.2 mmol) in water (12 mL), MeCN (6 mL), and MeOH (1 mL) at 25° C. was treated with Cs2CO3 (1.7 g, 5.2 mmol). After the mixture was stirred for 30 minutes, iodoethane (0.42 mL, 5.2 mmol) was added and the mixture was stirred at 60° C. for 40 hours before being cooled to room temperature. The solid was collected by filtration and washed with MeOH to give 6-(ethyloxy)-7-(methyloxy)-4(1H)-quinazolinone (560 mg, 49%). MS (m/z) 221.1 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH3:15])=O)(C)(C)C.Cl>ClCCl.C(OCC)C>[CH3:15][N:14]([CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: CN(CC1CCCN1C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CN(CC1CCCN1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 118.3 %

Procedure:
To a solution of 2-[(methanesulfonyl-methyl-amino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.63 g) in dichloromethane (10 mL) at room temperature was added hydrogen chloride (3.0 mL of a 2 M solution in diethyl ether). The reaction mixture was stirred at room temperature for 72 h and then reduced in vacuo to give N-methyl-N-pyrrolidin-2-ylmethyl-methanesulfonamide as a crystalline solid (0.49 g).
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:2]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].CC(C)([O-])C.[K+].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[F:35])[C:27]([O:29]CC)=[O:28].O>CN(C=O)C>[C:12]([O:11][C:9]([N:1]([CH2:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[F:35])[C:27]([OH:29])=[O:28])[C:2]([O:4][C:5]([CH3:6])([CH3:7])[CH3:8])=[O:3])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccc(F)c(CBr)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1cc(C(=O)O)ccc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.7 %

Procedure:
1.56 g of di-tert-butyl iminodicarboxylate was dissolved in 20.0 mL of DMF, and 804 mg of potassium tert-butoxide was added under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction liquid was added dropwise a solution (10.0 mL) of 1.70 g of ethyl 3-(bromomethyl)-4-fluorobenzoate in DMF, followed by stirring at room temperature overnight. The reaction liquid was poured to water, followed by extraction with ethyl acetate, and the organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 2.59 g of 3-{[bis(tert-butoxycarbonyl)amino]methyl}-4-fluorobenzoic acid.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([CH2:15]Br)[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=O)C.C(N(CC)CC)C.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CC(C)=O>[OH:4][C:5]1[CH:14]=[C:13]([CH2:15][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:12]([C:17]([F:18])([F:19])[F:20])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cc(C(F)(F)F)c(CBr)cc1OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1O
Reaction time: 18 h

Procedure:
To a solution of methyl 2-(acetyloxy)-4-(bromomethyl)-5-(trifluoromethyl)benzoate (may be prepared as described in Description 47; 240 mg, 0.68 mmol) in acetone (5 ml) was added triethylamine (0.19 ml, 1.35 mmol) and piperidine (0.09 ml, 0.88 mmol). The solution was stirred for 18 hours. The solvent was removed in vacuo and the residue was taken up in ethyl acetate (10 ml), washed with water (10 ml), dried (MgSO4) and the solvent removed in vacuo to give the title compound. 228 mg.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13]C(=O)C[Cl:16])[C@H:9]1[CH2:18][N:19]1[C:27]2[CH:26]=[CH:25][C:24]([C:28]#[N:29])=[CH:23][C:22]=2[C:21]2[CH2:30][C@H:31]([NH:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:32][C:20]1=2)=O)(C)(C)C.[Li+].[OH-]>CO.C(OCC)(=O)C>[ClH:16].[CH:37]([O:36][C:34](=[O:35])[NH:33][C@@H:31]1[CH2:32][C:20]2[N:19]([CH2:18][C@@H:9]3[C@H:10]([OH:13])[CH2:11][CH2:12][NH:8]3)[C:27]3[CH:26]=[CH:25][C:24]([C:28]#[N:29])=[CH:23][C:22]=3[C:21]=2[CH2:30]1)([CH3:39])[CH3:38]
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@@H]3[C@H](OC(=O)CCl)CCN3C(=O)OC(C)(C)C)c3ccc(C#N)cc23)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@H]3NCC[C@H]3O)c3ccc(C#N)cc23)C1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
A solution of (2R,3R)-3-(2-chloro-acetoxy)-2-((S)-7-cyano-2-isopropoxycarbonylamino-2,3-dihydro-1H-cyclopenta[b]indol-4-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 894.4 μmol) in MeOH (2 mL) is treated with 2 N LiOH solution (2 mL) and the suspension is stirred for 4 h at room temperature. The suspension is diluted with ethyl acetate (60 mL) and washed with water and brine. The organic portion is dried over sodium sulfate, filtered, and concentrated. The residue (0.39 g) is dissolved in 10 mL of MeOH (10 mL) and treated with 4 N HCl in 1,4-dioxane solution (10 mL). The solution is stirred for 2 h and concentrated in vacuo to afford 0.37 g (92%) of the title compound. LC-ES/MS m/z 383.2 [M+H]+, TR=1.86 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: OCCNCCO
Product: OCCN(CCO)CCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 5, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and diethanolamine were converted to yield 2-[[3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-(2-hydroxy-ethyl)-amino]-ethanol as white semisolid, MS: 451 (MH+, 1Br).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.[C:13](O)(=[O:25])[CH2:14]CCCCCCCCCC.C(O)(=O)CCCCCCCCCCCCC.C(O)CO>ClCCl>[C:1]([O:12][CH2:14][CH2:13][OH:25])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCC(=O)O
Solvent: OCCO
Solvent: ClCCl
Product: CCCCCCCCC(=O)OCCO
Reaction time: 216 h

Procedure:
Decanoic acid (C10 acid), dodecanoic acid (C12 acid), and tetradecanoic acid (C14 acid)--each of 100 mmol of C10, C12 and C14 acids were dissolved in 50 ml dichloromethane, and 300 mmol of ethylene glycol were added to the solutions. Several drops of H2 SO4 were added to the mixture. The reaction mixtures were stored at room temperature for 9 days. Isolation of the esters were carried out using the same procedure as that to isolate ethylene glycol monopelargonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[OH:28])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccccc1O
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1ccccc1O
Yield: 99 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.88 mmol) and o-aminophenol (110 mg, 1 mmol) to give 375 mg of the title compound (98%): mp 155° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.07 (s, 1H), 9.71 (bs, 1H), 9.36 (s, 1H), 7.72 (d, 1H, J=7.2 Hz), 7.24 (bs, 1H), 7.17 (bs, 1H), 6.95 (dt, 1H, J=2, 7.2 Hz), 6.85 (dd, 1H, J=2, 7.2 Hz), 6.76 (dt, 1H, J=7.2, 2 Hz), 5.17~5.26 (m, 1H), 3.14 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.80 (dm, 1H, J=17.1 Hz), 2.78 (dd, 1H, J=14.4, 9 Hz), 2.64 (dd, 1H, J=14.4, 4.5 Hz), 2.10 (dm, 1H, J=13.5 Hz), 1.78~1.92 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](C[CH2:8][CH2:9][CH:10]2[C:13]#[N:14])=[CH:5][C:4]=1[CH3:15].[CH2:16]([NH2:19])[CH2:17]N.C1(C)C=CC(S(O)(=O)=[O:27])=CC=1>>[NH:19]1[CH2:16][CH2:17][N:14]=[C:13]1[CH:10]1[C:11]2[C:6](=[CH:5][C:4]([CH3:15])=[C:3]([O:2][CH3:1])[CH:12]=2)[O:27][CH2:8][CH2:9]1
Reactant: NCCN
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cc2c(cc1C)CCCC2C#N
Product: COc1cc2c(cc1C)OCCC2C1=NCCN1

Procedure:
This compound was prepared in a manner analogous to that of Step G of Example 1, by the reaction of 0.5 gram (0.002 mole) of 7-methyl-6-methoxychromane-4-carbonitrile (iv) and 2 grams (0.008 mole) of the ethylenediamine salt of p-toluenesulfonic acid (prepared in Step F of Example 1). The reaction product was purified by column chromatography on Grade II basic alumina (3% water) using a 99:1 mixture of methylene chloride and methanol, respectively, as an eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 0.30 gram of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:7]=2)=[N:2]1.Cl[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[O:51][CH3:52].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:52][O:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[CH2:44][N:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[CH:7]=2)=[N:2]1
Reactant: COc1ccccc1CCl
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc[nH]n3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1Cn1ccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)n1
Temperature: 75 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
(S)-2-(1-((5-(1H-Pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (2.0 ml). 1-(Chloromethyl)-2-methoxybenzene (43 ml, 0.27 mmol) and cesium carbonate (200 mg, 0.61 mmol) were added and the mixture was stirred at 75° C. during 2 h. The reaction was poured into ice-water mixture, basified to pH 10 with sodium carbonate and extracted twice with ethyl acetate. The organics were combined and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to give 86 mg (83% yield, 93% purity) of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4](=O)NC(C)=C[CH:8]=1)#[N:2].[CH:11]([N-:14]C(C)C)(C)C.[Li+].CI.[OH-].[Na+].[O:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:11]([C:26]1[C:27](=[O:23])[NH:2][C:1]([CH:3]([CH3:4])[CH3:8])=[CH:24][CH:25]=1)#[N:14]
Reactant: Cc1ccc(C#N)c(=O)[nH]1
Reactant: CC(C)[N-]C(C)C
Reactant: C1CCOC1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Product: CC(C)c1ccc(C#N)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A solution of 3-cyano-6-methyl-2(1H)-pyridinone (10.0 g, 74.6 mmol) in anhydrous tetrahydrofuran (100 mL) was cooled to −78° C. under nitrogen and reacted slowly with lithium diisopropylamide solution (40 mL of 1.4 M and 85 mL of 2.0 M, 226 mmol total) via syringe. After warming to 0° C. and stirring 2 hours, methyl iodide (10 mL, 160 mmol) was added and the reaction stirred 18 hours at ambient temperature. The reaction was poured into 0.67 N NaOH (300 mL), the phases separated, the aqueous layer washed with diethyl ether, and the combined organic layers extracted with water. The combined aqueous layers were acidified to pH 4 with 6 N HCl and extracted with methylene chloride, and the methylene chloride layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (1:1 methylene chloride:ethyl acetate) giving the title compound as a light yellow solid (2.15 g, 18%). 1H NMR (300 MHz, CDCl3) δ 13.25 (br s, 1H), 7.84 (d, 1H, J=7.5 Hz), 6.23 (d, 1H, J=7.5 Hz), 3.00 (septet, 1H, J=7.0 Hz), 1.36 (s, 3H), 1.34 (s, 3H). Also recovered from the column was the mono-methylated side-product 3-cyano-6-ethyl-2(1H)pyridinone (5.50 g, 50%). which was used to make the title compound in Example 97. 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J=7.5 Hz, 1H), 6.23 (d, J=7.4 Hz, 1H), 2.76 (q, J=7.6 Hz, 2H), 1.35 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([N:18]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:17])=[CH:12][CH:11]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.O.NN>O1CCOCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([NH2:18])[CH3:17])=[CH:12][CH:11]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1-c1ccc(C(C)N2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: COc1ncc(F)cc1-c1ccc(C(C)N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
The organic phase was washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue chromatographed on silica gel to give to give 2-{1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-isoindole-1,3-dione (0.31 g, 0.82 mmol, 41%). To a solution of 2-{1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-isoindole-1,3-dione (0.31 g, 0.8 mmol) in dioxan/methanol (1:1, 10 ml) was added hydrazine hydrate (0.83 g, 46.5 mmol). The reaction was stirred at room temperature for 24 h. The solvent was evaporated and dichloromethane added. The resultant white solid was filtered off and dried to give 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethylamine (0.21 g, 0.8 mmol, 100%) as a clear oil. To a solution of 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethylamine (0.1 g, 0.4 mmol) in dichloromethane (2 ml) was added triethylamine (123 mg, 1.2 mmol) and 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonylchloride (111 mg, 0.45 mmol). The reaction mixture was agitated for 16 h and quenched with saturated aqueuos sodium bicarbonate solution. The organic phase was washed with water, brine and dried over anhydrous magneium sulfate. The residue was chromatographed on silica gel to give the title compound (42 mg, 0.1 mmol, 25%). 1H NMR (400 MHz, CDCl3): δ 8.00 (d, 1H), 7.45 (m, 3H), 7.35 (dd, 1H), 7.21 (d, 2H), 4.86 (d, 1H), 4.60 (q, 1H), 3.96 (s, 3H), 3.75 (s, 3H), 1.50 (b, 3H) ppm; MS (ESI) m/z: 459.3 [M+H]+.