Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]1[C:8]([O:10][C:11](=O)[CH:2]21)=[O:9].Cl>O>[C:4]12[CH2:7][CH:1]([CH2:6][CH2:5]1)[CH:2]1[C:3]=2[C:8](=[O:9])[O:10][CH2:11]1
Reactant: O=C1OC(=O)C2C3C=CC(C3)C12
Agent: Cl
Solvent: O
Product: O=C1OCC2C1=C1CCC2C1
Yield: 45 %

Procedure:
Using 164.0 g (1.00 mol) of 5-norbornene-2,3-dicarboxylic anhydride, reduction was carried out in the same manner as in Example A13. Thereafter, water was added to the reaction solution, and hydrochloric acid was further added thereto until pH became 0.5. The mixture was extracted twice with hexane, and the combined organic extracts were washed with water. When the hexane layer was separated from the water layer, an emulsion layer appeared in the interface, and therefor the separation was significantly difficult. Although the hexane layer was concentrated with an evaporator until no evaporated products were evaporated, a product of interest could not be isolated. In the analysis of DMF concentration by gas chromatography, remaining DMF represented 15% to the total mass. So as to eliminate the DMF, hexane and water were added to the flask, and after fully stirring, the mixture was separated in layers. The hexane layer was subjected to an evaporator again to concentrate it until no evaporated products were evaporated. After the operation to eliminate the DMF was repeated twice, the concentration of remaining DMF represented 3% to the total mass. This time, it was observed that a highly adhesive white solid was present in the flask, and the removal of this solid was difficult. This solid was analyzed by gas chromatography, and as a result, 67.6 g (0.450 mol) of 4-oxatricyclo[5.2.1.02,6]decen-3-one was obtained at a yield of 45%. When compared with Example A13, the yield was significantly decreased, and further, the operation became more complicated.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:12]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: C1CCNC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: O=C(O)Cc1ccccc1N1CCCC1
Temperature: 90 °C

Procedure:
A mixture of 2-(2-bromophenyl)acetic acid (10.7 g), pyrrolidine (20 cc) and copper acetate (1.66 g) is heated for 2 hours, with stirring, at 90° C.; after returning to ambient temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 5 cm, height 55 cm), eluting with 1,2-dichloroethane (1,000 cc) and then with mixtures of 1,2-dichloroethane and methanol [(proportions by volume): 1,000 cc (98/2), 2,000 cc (97/3), 1,000 cc (96/4) and 1,000 cc (95/5)] and collecting 250 cc fractions. Fractions 21 to 29 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 2-[2-(1-Pyrrolidinyl)phenyl]acetic acid (2 g) is obtained in the form of an orange oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:37])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][CH3:36])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:35]([C:31]1[CH:30]=[C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:37])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:34]=[CH:33][N:32]=1)[CH3:36]
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (2-{3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M138) (0.27 g, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (158 mg, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C:35]([CH3:40])([CH2:38][OH:39])[CH2:36][OH:37])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C:35]([CH2:38][OH:39])([CH3:40])[CH2:36][OH:37])(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: CC(CO)(CO)NS(=O)(=O)c1ccccc1Br
Product: CC(CO)(CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-bromo-N-(1,3-dihydroxy-2-methylpropan-2-yl)benzenesulfonamide. MS (ESI): mass calcd. for C20H21FN4O4S, 432.13; m/z found, 433.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[S:5][C:6]1[CH:7]=[CH:8][C:9]([N+:18]([O-:20])=[O:19])=[CH:10][C:11]=1[C:12]2=O.B.C1COCC1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[S:5][C:6]1[CH:7]=[CH:8][C:9]([N+:18]([O-:20])=[O:19])=[CH:10][C:11]=1[CH2:12]2
Reactant: COc1cccc2c(=O)c3cc([N+](=O)[O-])ccc3sc12
Agent: B
Solvent: C1CCOC1
Product: COc1cccc2c1Sc1ccc([N+](=O)[O-])cc1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To a cooled (0° C.) suspension of 5-methoxy-2-nitro-thioxanthene-9-one (24.46 g, 85.13 mmol) in anhydrous tetrahydrofuran (40 ml) under nitrogen atmosphere, was added drop wise borane-THF complex (170 ml, 1.0M in THF). The mixture was allowed to warm to room temperature with stirring overnight. The reaction mixture was cooled (0° C.) and the excess borane was quenched with acetone. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (1:1, dichloromethane/hexane) to give the title compound (11.59 g, 50%) as a bright yellow amorphous solid. 1HNMR (300 MHz, DMSO-d6): δH=3.86 (3H, s), 4.03 (2H, s), 7.00 (2H, dd), 7.28 (1H, t), 7.73 (1H, d), 8.05 (1H, dd), 8.28 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:14][O:15][CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCC1CCCCC1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of 0.58 g (1.48 mmol) 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) in 6 mL N,N-dimethylformamide, 71 mg (1.5 mmol, 55% dispersion in mineral oil) sodium hydride and after 5 min. 0.32 g (1.78 mmol) bromomethylcyclohexane were added. The reaction mixture was warmed to 50° C. and after 4 h another 71 mg sodium hydride and 0.32 g (1.78 mmol) bromomethylcyclohexane were added. A third batch sodium hydride and bromomethylcyclohexane were added after 3 h. After stirring overnight the reaction mixture was poured on water and ethyl acetate, extracted, the aqueous phase extracted twice with ethyl acetate and the aqueous phase extracted twice with ethyl acetate. The combined organic layers were washed twice with water and once with brine, dried over magnesium sulfate and evaporated. The crude product was purified by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethylacetate (1:0 to 4:1) to yield the title compound as a white solid (39%). MS (Turbo Spray): m/z=487.3 [M+H].
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1.F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([CH:6]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1)#[N:12]
Reactant: N#Cc1ccc(F)cc1
Reactant: N#Cc1ccc(Cn2cncn2)cc1
Product: N#Cc1ccc(C(c2ccc(C#N)cc2)n2cncn2)cc1

Procedure:
U.S. Pat. No. 4,978,672 discloses 4-[alpha-(4-cyanophenyl)-1-(1,2,4-triazolyl)-methyl]benzonitrile and a process for its preparation comprising reacting 4-bromomethyl benzonitrile with 1,2,4-triazole to yield 4-[1-(1,2,4-triazol-1-yl)methyl]benzonitrile. 4-[1-(1,2,4-triazol-1-yl)methyl]benzonitrile is then reacted with 4-fluorobenzonitrile to give 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile (letrozole).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][C:4]1([C:13]([F:16])([F:15])[F:14])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5]1.[N+:19]([O-])([OH:21])=[O:20].S(=O)(=O)(O)O>C(Cl)Cl>[N+:19]([C:11]1[CH:10]=[CH:9][C:7]2[O:8][C:4]([CH2:3][C:2]([F:1])([F:17])[F:18])([C:13]([F:15])([F:14])[F:16])[O:5][C:6]=2[CH:12]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)CC1(C(F)(F)F)Oc2ccccc2O1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 54.4 g of 2-(2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole in 75 ml of methylene chloride was added dropwise at 10° C. to a mixture of 40 ml of 65% by weight nitric acid and 40 ml of concentrated sulphuric acid. The reaction mixture was subsequently stirred for 1 hour at room temperature and then poured into ice-water, the organic phase was separated off and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with water and dried and the readily volatile components were removed. The residue consisted of 95 g of product (=86% of theory) melting at 87° to 88° C. The NMR spectra showed the following characteristic absorptions: 19F NMR: -59.0 and -69.4 ppm. 1H NMR: 3.10 ppm.
Reaction SMILES: [NH2:1][C@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1)=O.B.C1COCC1.Cl>C1COCC1.O>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:9][CH2:10][N:5]([CH2:3][C@H:2]([NH2:1])[CH2:19][C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[CH2:6][CH2:7]1
Reactant: COc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccncc2)CC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1N1CCN(C[C@H](N)Cc2ccncc2)CC1
Temperature: 25 °C

Procedure:
To a solution of (2R)-2-Amino-1-[4-(2-methoxy-phenyl)-piperazin-1-yl]-3-pyridin-4-yl-propan-1-one (6.18 g; 18 mmol, from Example 7) in THF (60 mL) was added, dropwise, BH3.THF (1.0M/THF) (73 mL; 73 mmol). The mixture was stirred at reflux for 2 hours, cooled to ambient temperature, cautiously treated with 6N HCl (45 mL), stirred at ambient temperature for 1 hours. The mixture was then diluted with water (100 mL), concentrated on a rotary evaporator to remove THF, and the aqueous residue washed with ether (30 mL). The aqueous layer was rendered basic (pH 9–10) with concentrated NH4OH, and the product extracted into dichloromethane (3×75 mL). The combined dichloromethane layers were washed with brine, dried over MgSO4, filtered, and the solvent removed in vacuo to yield the title compound as a free base (4.85 g.; 82%). The analytical sample was converted to the hydrochloride salt with ethereal HCl to yield an off-white crystalline solid, m.p. 177–178° C.; MS (+) ESI, [M+H]+ @ m/z 327; 1H NMR, 400 MHz, DMSO-d6. Analysis for C19H26N4O.HCl.0.3H2O.0.3 C2H6O Calculated: C, 61.61; H, 7.75; N, 14.66 Found: C, 61.45; H, 7.80; N, 14.49.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.Cl[S:14]([OH:17])(=[O:16])=[O:15]>ClCCl>[CH3:12][C:1]1[CH:6]=[C:5]([S:14]([OH:17])(=[O:16])=[O:15])[CH:4]=[CH:3][C:2]=1[N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccccc1N1CCCC1
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)O)ccc1N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a cooled (0° C.) solution of 119 (1.24 g; 7.7 mmol) in anhydrous dichloromethane (38 mL) was added chlorosulfonic acid (0.61 mL; 9.24 mmol) dropwise (1 mL/minutes). The reaction mixture w as allowed to gradually warm to room temperature while stirring overnight. The reaction mixture was concentrated under reduced pressure. The resulting oil w as taken up in diisopropyl ether (10 mL) and aqueous hydrochloric acid (0.5 mL; 2N) then stirred vigorously at room temperature for 2 hours. The organic phase was separated and concentrated under reduced pressure to yield the desired compound as an amber oil (1.8 g).
Reaction SMILES: [C:1]1([CH:7]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([CH:26]([N:33]=[C:34]=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH:26]([NH:33][C:34]([N:17]1[CH2:16][CH2:15][N:14]([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19][CH2:18]1)=[O:35])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: ClCCl
Product: O=C(NC(c1ccccc1)c1ccccc1)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of diphenylmethyl piperazine (0.3 g, 1.18 mmol) in dry CH2Cl2 (10 ml) was added diphenylmethyl isocyanate (0.22 ml, 1.18 mmol) drop wise under nitrogen. The resulting mixture was stirred at room temperature over night. Removal of solvent under reduced pressure followed by column chromatography using hexane:ethyl acetate (3:1) gives the desired product in 80% yield.
Reaction SMILES: [C:1]1([C:7]2([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[O:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]N1C(=O)CCC1=O>CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:8][CH2:9][CH2:10][O:11]2)=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C2(c3ccccc3)OCCO2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(C2(c3ccccc3)OCCO2)cc1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
To a round-bottom flask were added 12 (3.54 g, 14.7 mmol, 1.0 equiv.), N-bromosuccinimide (2.9 g, 16.2 mmol, 1.1 equiv.), AIBN (48 mg, 0.29 mmol, 0.02 equiv.), and CCl4 (60 mL, 0.25 M). The reaction mixture was stirred at reflux for 6.5 hours. The reaction mixture was cooled to room temperature. The succinimide was filtered and washed with CC14. The filtrate was concentrated and crystallized from EtOAc/hexanes to yield 13 (2.57 g, 55%) as a white solid. 1H-NMR (500 MHz, CDCl3) δ 7.56-7.53 (m, 4H), 7.38-7.35 (m, 4H), 7.33-7.29 (m, 1H), 4.48 (s, 2H), 4.08 (s, 4H). 13C-NMR (125 MHz, CDCl3): δ 142.4, 141.8, 137.4, 128.8, 128.1, 128.1, 126.5, 125.9, 109.0, 64.8, 33.1.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:7]([OH:16])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].[CH2:18]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22]Cl)[CH3:19]>>[CH2:1]([N:5]1[CH2:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:7]([O:16][CH2:19][CH2:18][N:20]([CH2:24][CH3:25])[CH2:21][CH3:22])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CC(c2ccccc2)=C(O)C1=O
Reactant: CCN(CC)CCCl
Product: CCCCN1CC(c2ccccc2)=C(OCCN(CC)CC)C1=O

Procedure:
23.1 g. 1-n-butyl-3-hydroxy-4-phenyl-3-pyrrolin-2-one is reacted with 20.3 g. β-diethylaminoethyl chloride in a manner analogous to that described in Example 1. The 1-n-butyl-3-(β-diethylaminoethoxy)-4-phenyl-3-pyrrolin-2-one obtained in the form of the free base is reacted in diethyl ether with oxalic acid to give the crystalline oxalate. The yield is 24.2 g. (58% of theory); m.p. 120°-121° C.; after recrystallization from methyl ethyl ketone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=O)[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7](O)=[O:8].O.[NH2:17][NH2:18]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7](=[O:8])[NH:18][N:17]=[CH:14]2
Reactant: NN
Reactant: COc1cc(C=O)c(C(=O)O)cc1OC
Solvent: O
Solvent: CCO
Product: COc1cc2cn[nH]c(=O)c2cc1OC

Procedure:
4,5-Dimethoxyphthalaldehydic acid (10 g.) and hydrazine hydrate (2.4 ml.) in ethanol (150 ml.) were heated under reflux for 20 hours during which time a white crystalline solid formed. The mixture was cooled in an ice bath, filtered and the resulting product dried to give crude 6,7-dimethoxyphthalazin-1-one (7 g.). A sample was crystallized from water yielding colorless needles, m.p. 254°-256° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[O:18]1[C:22]2([CH2:27][CH2:26][CH:25]([NH:28][C@@H:29]([C:31]([O:33][CH3:34])=[O:32])[CH3:30])[CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:28]([CH:25]2[CH2:26][CH2:27][C:22]3([O:18][CH2:19][CH2:20][O:21]3)[CH2:23][CH2:24]2)[C@@H:29]([C:31]([O:33][CH3:34])=[O:32])[CH3:30])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: COC(=O)[C@@H](C)NC1CCC2(CC1)OCCO2
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)[C@@H](C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
To a stirred mixture of 2,4-dichloro-5-nitropyrimidine (4, 12 g, 62.1 mmol), potassium carbonate (11.7 g, 84.78 mmol) in acetone (100 mL) was added methyl N-1,4-dioxaspiro[4.5]dec-8-yl-D-alaninate (13.8 g, 62.1 mmol) at rt. The reaction mixture was stirred for 16 h at rt. The bulk of solvent was removed under reduced pressure to give a residue, which was diluted with ethyl acetate (100 mL), washed with water, dried over sodium sulfate. The solvent was evaporated to give a crude material, which was then purified by silica gel flash chromatography (eluent: ethyl acetate-hexane mixture (v:v=5:95)) to afforded the desired product (10.1 g). 1HNMR (300 MHz, CDCl3): δ 1.55-1.64 (m, 3H), 1.70-1.99 (m, 6H), 2.05-2.20 (m, 3H), 3.06-3.15 (m, 1H), 3.75 (s, 3H), 3.99 (t, 4H), 8.61 (s, 1H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[CH:11]([CH2:12][CH3:13])[CH2:10]1>C(O)C>[CH2:1]([NH:8][CH2:10][CH:11]([OH:9])[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCC1CO1
Solvent: CCO
Product: CCC(O)CNCc1ccccc1
Temperature: 150 °C

Procedure:
To a solution of benzylamine (29.65 g, 277.0 mmol) in ethanol (40 mL) was added 1,2-epoxybutane (4 g, 55.47 mmol) and the mixture was heated to 150° C. for 2 h in a autoclave. It was concentrated and distilled at 140-150° C./2 mm Hg to give product as color less liquid, which slowly crystallizes at room temperature after 2 days. Yield: 8.5 g (85%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[N:11]1([CH2:17][CH2:18][OH:19])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:14]2[CH2:15][CH2:16][N:11]([CH2:17][CH2:18][OH:19])[CH2:12][CH2:13]2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: OCCN1CCNCC1
Product: O=C(c1ccc(Br)cn1)N1CCN(CCO)CC1

Procedure:
The title compound was prepared from 5-bromo-pyridine-2-carboxylic acid (1.0 g, 5.0 mmol) and 2-piperazin-1-yl-ethanol (1.0 g, 7.7 mmol) according to Method A (Example 89). After the removal of solvent, the residue was triturated in hexane-Et2O (5:1 v/v) and the white solid filtered (1.0 g, 65%).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[C:16]3[C:23]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[CH:22][S:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:7]=[N:6][CH:5]=1.[OH-].[K+].C(O)(=O)C>CO>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]2[C:16]3[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8]4[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=4)[C:3]([OH:31])=[O:2])=[N:20][CH:19]=[N:18][C:17]=3[S:21][CH:22]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)c1cncc(OCCCCc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1cncc(OCCCCc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82139.1 %

Procedure:
A mixture of methyl-5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nicotinate (0.010 g, 0.023 mmol) and potassium hydroxide (0.0112 g, 0.200 mmol) in methanol (0.5 mL) was stirred at room temperature for 12 h. Acetic acid (200 mg, 3.33 mmol) was then added, and the reaction solvent was removed by evaporation. The product was purified by column chromatography over silica gel using 5% methanol in dichloromethane as eluant to afford 8 g (83%) 5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nicotinic acid hydroformate as white solid. MS [M+H]=424.1, LC/MS (EI) tR 3.89 min (Method D), 1H NMR (10% MeOD/CDCl3) δ (ppm) 8.94 (s, 1H), 8.73 (s, 1H), 8.28 (s, 1H), 7.68 (s, 1H), 7.40-7.30 (m, 3H), 7.10 (t, J=8.4 Hz, 2H), 3.84 (t, J=6.3 Hz, 2H), 2.68 (t, J=7.2 Hz, 2H), 1.75-1.59 (m, 2H), 1.59-1.45 (m, 2H)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)[CH:14]=[O:15]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[CH:10]=[CH:9][N:8]([CH2:2][C@H:1]2[CH2:5][CH2:6][CH2:14][O:15]2)[C:7](=[NH:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccnc(N)c1
Reactant: CN(C)C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Product: CC(C)(C)c1ccn(C[C@H]2CCCO2)c(=N)c1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A mixture of 4-tert-butylpyridin-2-amine (1.0 g, 6.7 mmol, LeadGen Labs), Example 11A (2.0 g, 8.0 mmol), and tetrabutylammonium iodide (1.2 g, 3.3 mmol) in N,N-dimethylformamide (1.3 mL) was heated at 95° C. for 16 hours. The reaction was incomplete as monitored by LC/MS. One more equivalent of both Example 11A and tetrabutylammonium iodide were added. After stirring at 95° C. for 16 hours, the reaction mixture was cooled and quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with dichloromethane (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 235 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:5]2[N:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: OCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Yield: 69.5 %

Procedure:
(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methanol 6 (1 g) was reacted with pyridinium chlorochromate (1.1 eq) overnight at room temperature in dichloromethane (25 mL). The reaction was filtered thru celite and run thru a silica plug to get 0.69 g of 2-chloro-4-morpholinopyrido[3,2-d]pyrimidine-6-carbaldehyde as a yellow solid after evaporation.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][CH:3]1[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>CO.[OH-].[OH-].[Pd+2]>[OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCC1CN(Cc2ccccc2)CCC1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CNCCC1O
Yield: 99.5 %

Procedure:
A solution of 1,1-dimethylethyl {[4-hydroxy-1-(phenylmethyl)-3-piperidinyl]methyl}carbamate (3.7 g, 11.56 mmol) in methanol (70 ml) was stirred under hydrogen at room temperature with 20% palladium hydroxide/carbon (moist, 0.7 g) overnight. After filtration through kieselguhr, the methanol was evaporated to afford the desired product (2.65 g, 100%).