Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:18])[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([NH2:46])[C:41]=1[NH2:47].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)CCl>[CH2:1]([O:8][C:9](=[O:10])[N:11]([CH2:12][CH2:13][CH2:14][C:15](=[O:17])[NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([O:39][CH3:38])[C:41]=1[NH2:47])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CCCC(=O)O)C(=O)OCc1ccccc1
Reactant: COc1cccc(N)c1N
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)CCCN(C)C(=O)OCc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1.40 g 4-(benzyloxycarbonyl-methyl-amino)-butyric acid (obtained from 4-(methylamino)butyric acid and benzylchloroformate) in 25 mL THF were added 2.9 mL of DIPEA, 0.97 g of HOBt and 1.38 g EDC. After stirring for 5 min 0.80 g of 3-methoxy-benzene-1,2-diamine were added and the mixture was stirred for 3 h at rt. Sat. aq. NaHCO3 solution was added, the phases were separated and the organic phase was washed with brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:21]([C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1)([CH3:24])([CH3:23])[CH3:22]>CO>[C:21]([C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=1)[O:31][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)c1cccc(O)c1
Solvent: CO
Product: COC(=O)C(Oc1cccc(C(C)(C)C)c1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
In an identical manner as in Example 39, 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate is reacted with 3.75 g of 3-tert-butylphenol in methanol to give a yellow oil. Fractional bulb-to-bulb distillation gives the product as a viscous yellow oil (182° C. @ 0.05 mm).
Reaction SMILES: N([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]3[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[CH:17][N:16]=2)[N:9]=1)C(N)=N.[C:30]([O:33]C(=O)C)(=O)[CH3:31].[C:37]([O:45]C(=O)C1C=CC=CC=1)(=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>N1C=CC=CC=1>[C:30]([N:14]=[C:15]([NH2:20])[NH:16][CH:10]([C:8]1[N:9]=[CH:5][S:6][CH:7]=1)[S:11][CH2:12][CH2:13][NH:14][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[CH:17][N:16]=1)(=[O:33])[CH3:31].[C:37]([N:14]=[C:15]([NH2:20])[NH:16][CH:10]([C:8]1[N:9]=[CH:5][S:6][CH:7]=1)[S:11][CH2:12][CH2:13][NH:14][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[CH:17][N:16]=1)(=[O:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(Cc2cnc(NCCSCc3csc(NC(=N)N)n3)[nH]c2=O)cn1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)N=C(N)NC(SCCNc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1)c1cscn1
Product: Cc1ccc(Cc2cnc(NCCSC(NC(N)=NC(=O)c3ccccc3)c3cscn3)[nH]c2=O)cn1

Procedure:
Reaction of 2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone with acetic anhydride or benzoic anhydride in pyridine gives 2-[2-(2-acetylguanidino-4-thiazolylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone and 2-[2-(2-benzoylguanidino-4-thiazolylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7](=O)[CH:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13])[CH3:3].C(N(C(C)C)CC)(C)C.[P:35](Cl)([O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36].FC(F)(F)S([O-])(=O)=O.[CH3:60][S:61][C:62]1[N:66]([CH3:67])[CH:65]=[CH:64][N+:63]=1[CH2:68][CH2:69][SH:70]>C(#N)C.O>[C:38]1([O:37][P:35]([O-:1])([O:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:36])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[CH3:60][S:61][C:62]1[N:66]([CH3:67])[CH:65]=[CH:64][N+:63]=1[CH2:68][CH2:69][S:70][C:7]1[CH2:6][C@H:5]2[N:9]([C:10](=[O:11])[C@@H:4]2[C@H:2]([OH:1])[CH3:3])[C:8]=1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: CSc1n(C)cc[n+]1CCS
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CSc1n(C)cc[n+]1CCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Product: O=P([O-])(Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a solution of p-nitrobenzyl (5R, 6S)-6-[1-(R)-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (1.40 g, 4.0 mmol) in 50 mL of dry acetonitrile, at 0° C. under N2, was added dropwise diisopropylethylamine (0.76 mL, 4.4 mmol) followed by diphenyl chlorophosphate (0.91 mL, 4.1 mmol). After stirring the reaction mixture at room temperature for 1 h, diisopropylethylamine (0.76 mL, 4.4 mmol) was added and then a solution of 2-methylthio-3-methyl-1-(2-mercaptoethyl)imidazolium trifluoromethanesulfonate (2.0 g, 5.9 mmol) in 5 mL of acetonitrile was added dropwise. The reaction mixture was kept at room temperature for 1.5 h and was then concentrated in vacuo to give a gum. This gum was taken up in H2O and applied to a C18 reverse-phase column. Elution with H2O, then 20% acetonitrile-H2O and finally 30% acetonitrile-H2O, followed by lyophilization of the appropriate fractions afforded the product (0.90 g, 30%) as a light yellow solid. ir(KBr) νmax : 3380 (br, OH), 1770 (β-lactam CO) cm-1 ; 'Hnmr (d6 -acetone) δ: 8.35 (br s, 1H), 8.24, 7.78 (AB q, J=8.8 Hz, 4H, aromatic), 7.89 (br s, 1H), 7.25-6.91 (m, 10H, diphenylphosphate), 5.50, 5.25 (ABq, J=12 Hz, 2H, benzylic), 4.75-4.27 (m, 3H), 4.03 (s, 3H, N-Me), 4.15-2.75 (m, 8H), 2.53 (s, 3H, S-Me), 1.22 (d, J=6.2 Hz, 3H, --CHMe).
Reaction SMILES: [C:1]([C:9]1[NH:10][CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15][C:16](Br)([C:22]([O:24]CC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.C(B([CH2:35][CH3:36])CC)C.O=O>CS(C)=O.O>[C:1]([C:9]1[N:10]2[C:15](=[CH:14][CH:13]=1)[C:16]([C:22]([O:24][CH2:35][CH3:36])=[O:23])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCB(CC)CC
Reactant: CCOC(=O)C(Br)(CCc1cc[nH]c1C(=O)c1ccccc1)C(=O)OCC
Agent: O=O
Agent: OO
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(C(=O)c3ccccc3)ccc21

Procedure:
To a mixture of a compound of formula VII, preferably 2-benzoyl-[3-bromo-3,3-di(ethoxycarbonyl)propyl]pyrrole, in a suitable solvent, is added an alkyl radical. A preferred alkyl radical, the methyl radical, is derived from the reaction of ferrous sulfate and hydrogen peroxide in dimethyl sulfoxide. In an alternative preferred embodiment, the alkyl radical is derived from a trialkylborane, preferably triethylborane, with oxygen (air) in a nonpolar solvent. The reaction mixture is allowed to stir until the reaction is complete. The reaction mixture is poured into water and extracted with a polar solvent, such as methylene chloride or diethyl ether. The combined organic extracts are washed, dried and concentrated under reduced pressure to yield a compound of formula I, preferably diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate, which may be isolated by conventional means.
Reaction SMILES: [N:1]([C:4]1[C:9]([I:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[Cl:12])=[N+:2]=[N-:3].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]#[N:23])=[CH:17][CH:16]=1.C[O-].[Na+]>C(O)C>[Cl:12][C:5]1[CH:6]=[C:7]([Cl:11])[CH:8]=[C:9]([I:10])[C:4]=1[N:1]1[C:22]([NH2:23])=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:3]=[N:2]1
Reactant: [N-]=[N+]=Nc1c(Cl)cc(Cl)cc1I
Reactant: COc1ccc(CC#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nnn(-c3c(Cl)cc(Cl)cc3I)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 9.8 %

Procedure:
To a stirred and ice-cooled solution of 2-azido-1,5-dichloro-3-iodo-benzene (0.500 g, 1.5928 mmol) and 4-methoxyphenylacetonitrile (0.29 g, 1.9114 mmol) in absolute ethanol (6 ml), an ice-cooled solution of sodium methoxide (0.129 g, 2.3892 mmol) in absolute ethanol (4 ml) is added drop-wise and the mixture is allowed to reach room temperature spontaneously overnight. The resulting reaction mixture is evaporated and the gummy residue (0.740 g, 100% mass balance) is purified by column chromatography over silica gel (60-120 mesh) eluting with 0-15% ethyl acetate in hexane, to obtain the title compound as a brown solid (0.072 g, 10% yield). M.p. 72.5-73.6° C. LC-ESI-HRMS of [M+H]+ shows 460.9425 Da. Calc. 460.943317 Da, dev. −1.8 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[CH3:29][S:30]([OH:33])(=[O:32])=[O:31]>C(OCC)(=O)C.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[S:30]([O-:33])(=[O:32])(=[O:31])[CH3:29]
Reactant: CS(=O)(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
3.79 g of Donepezil is dissolved in 70 ml of ethyl acetate, and a solution of methanesulfonic acid (0.65 ml) in absolute ethanol (35 ml) is slowly added with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 181.9° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CO.O.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>[CH3:9][C:10]1[CH:11]=[C:12]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: Nc1cnc(Br)cn1
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: C1COCCO1
Solvent: CO
Product: Cc1ccc(-c2cnc(N)cn2)cc1C
Temperature: 110 °C
Reaction time: 4.5 h

Procedure:
To a solution of 5-bromopyrazin-2-amine (4 g, 22.99 mmol, 1.00 equiv) in 1,4-dioxane (68 mL) and methanol (23 mL) was added 3,4-dimethylphenylboronic acid (3.52 g, 23.47 mmol, 1.02 equiv), sodium carbonate (4.872 g, 45.96 mmol, 2.00 equiv) in water (23 mL), and Pd(PPh3)4 (532 mg, 0.46 mmol, 0.02 equiv) and the resulting solution was stirred for 4.5 h at 110° C. in an oil bath. The resulting mixture was concentrated under vacuum, diluted with 200 mL of ethyl acetate, washed with 2×100 mL of brine, dried over anhydrous sodium sulfate and then concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether/ethyl acetate=10:1˜1:1, then with dichloromethane/methanol (10:1˜5:1). The collected fractions were combined and concentrated under vacuum. This resulted in 4.82 g (crude) of 5-(3,4-dimethylphenyl)pyrazin-2-amine as a yellow solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:3]=[CH:2][C:1]([O:5][CH3:6])=[O:4])=[CH:10][CH:9]=1
Reactant: C#CC(=O)OC
Reactant: Oc1ccc(Cl)cc1
Product: COC(=O)C=COc1ccc(Cl)cc1

Procedure:
Following the method of Example 14, methyl propiolate and 4-chlorophenol are reacted to yield methyl 3-(4-chlorophenoxy)-2-propenoate.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[S:22][C:21]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:23])[C:16]=3[CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S1C2C=CC=NC=2C=C1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](C[N:40]3[C@H:45](C2)[C:44]2[NH:53][C:54]4[CH:59]=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[ClH:23].[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[S:22][C:21]3[CH:20]=[CH:19][N:18]=[C:17]([N:40]4[CH2:45][CH2:44][NH:53][CH2:54][CH2:59]4)[C:16]=3[CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Reactant: CC(C)c1ccc(NS(=O)(=O)c2cc3c(Cl)nccc3s2)cc1
Agent: c1cnc2ccsc2c1
Solvent: CC#N
Product: CC(C)c1ccc(NS(=O)(=O)c2cc3c(N4CCNCC4)nccc3s2)cc1
Product: Cl

Procedure:
4-Chloro-thieno[3,2-c]pyridine-2-sulfonic acid (4-isopropyl-phenyl)-amide (0.201 mmol, 1 equiv.) was used as the thienopyridine in Method H-L. Yield: 6.9 mg HPLC: tR=3.255 (System: 5% to 50% ACN in 3 min, C8), Purity: 95%, LC/MS: tR=1.255 (System: 30% to 60% ACN in 1.5 min, Hypersil BDS), Purity: 98%. MS: 417 (M+1). 1H NMR (270 MHz, CH3OH-d4) δ ppm 1.18 (d, J=6.86 Hz, 6H) 2.83 (m, 2H) 3.52 (m, 4H) 4.00 (m, 4H) 7.14 (m, 3H) 7.75 (d, J=6.60 Hz, 1H) 8.02 (m, 1H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:34][C:35]#[N:36].O>C1COCC1>[OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:34][C:35]#[N:36])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(O)cc1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(OCC#N)cc1
Yield: 52.6 %

Procedure:
To the phenol prepared in example 91 (608 mg, 1.5 mmol) in THF (20 mL) at 0° C. was addded sodium hydride (66 mg of a 60% dispersion in oil, 1.66 mmol). After ten minutes bromoacetonitrile (199 mg, 1.66 mmol) was added. The suspension was stirred at room temperature whereupon another portion of bromoacetonitrile (360 mg, 3 mmol) was added and stirring continued until the reaction was complete by TLC. Water (50 mL) was added to the reaction and the two layers separated. The aqueous phase was extracted with ether (2×40 mL) and the combined organic phases dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 10% MeOH/CHCl3 to provide 350 mg (53%) of product. Anal. Calcd for C27H30N3O3: C, 67.56; H 6.30; N, 8.75. Found: C, 67.39; H, 6.51; N. 8.49.
Reaction SMILES: S(O[CH2:6][C:7]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)(C)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:26]([CH2:6][C:7]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=[N+:27]=[N-:28]
Reactant: COC(=O)c1ccc(COc2cc(Cl)ccc2COS(C)(=O)=O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2CN=[N+]=[N-])cc1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 74.6 %

Procedure:
To a solution of methyl 4-(2-mesyloxymethyl-5-chlorophenoxymethyl)benzoate (628 mg; prepared in Reference Example 48.) in DMF (5.0 ml), sodium azide (530 mg) was added in a stream of argon. The mixture was stirred for 40 minutes at 60° C. The reaction mixture was diluted with ethyl acetate. The impurity was filtered with celite. The filtrate was washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt =10:1) to give the title compound (404 mg) having the following physical data.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)=[O:11]
Reactant: COC(OC)N(C)C
Reactant: CCc1ccc(C(C)=O)cc1
Product: CCc1ccc(C(=O)C=CN(C)C)cc1

Procedure:
A mixture of 50 g. of 4'-ethylacetophenone and 50 ml. of dimethylformamide dimethylacetal is refluxed for 16 hours. Evaporation gave a thick oil which crystallized on the addition of hexane, m.p. 80°-81° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([CH3:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:15]N1C(=O)CCC1=O.C(N(CC)C(C)C)(C)C.P([O-])(OCC)(OCC)=O>ClCCCl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:13][C:11]1[C:10]([F:14])=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[CH:12]=1
Reactant: CCOC(=O)c1cc(F)c(C)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CCOP(=O)([O-])OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(F)c(CBr)cc1F
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 88.7 %

Procedure:
To a solution of ethyl 2,5-difluoro-4-methylbenzoate (Preparation 18, 4.674 g, 23.35 mmol) in 1,2-dichloroethane (70 mL) were added N-bromosuccinimide (4.57 g, 25.68 mmol) and benzoyl peroxide (56 mg, 0.23 mmol) and the mixture was heated to 70° C. for 2 days. The reaction mixture was allowed to cool, quenched with saturated aqueous sodium thiosulfate (20 mL) and diluted with water (50 mL). The organic layer was separated and the aqueous layer extracted with DCM (2×80 mL). The combined organics were washed with saturated aqueous sodium hydrogen carbonate, followed by brine, then filtered through a phase separator and concentrated in vacuo. The resulting yellow oil was redissolved in EtOAc (70 mL), and N,N-diisopropylethylamine (4.04 mL, 23.35 mmol) was added. The mixture was cooled to 0° C., and diethyl phosphate (2.29 mL, 23.35 mmol) was added. After stirring at 0° C. for 90 minutes, LCMS indicated complete conversion of the dibromomethyl impurity to the desired mono-bromomethyl product. The reaction was quenched at 0° C. with water (70 mL), followed by aqueous hydrochloric acid (2N, 10 mL). The organic layer was separated, washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to yield a yellow residue. The residue was purified by silica gel chromatography eluting with 0 to 3% EtOAc in heptane to afford the title compound as a clear oil (5.78 g, 89%):
Reaction SMILES: Cl.CN[O:4][CH3:5].C[CH2:7][N:8](C(C)C)C(C)C.C[Al](C)C.[F:19][CH:20]([F:41])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31](=[O:36])[C:30]([C:37]([O:39]C)=O)=[N:29]1>C(Cl)Cl>[F:41][CH:20]([F:19])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[C:33]([O:4][CH3:5])=[C:32]([O:34][CH3:35])[C:31](=[O:36])[C:30]([C:37]([NH:8][CH3:7])=[O:39])=[N:29]1
Reactant: CNOC
Reactant: COC(=O)c1nn(-c2ccccc2OC(F)F)cc(OC)c1=O
Reactant: CCN(C(C)C)C(C)C
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)c1nn(-c2ccccc2OC(F)F)c(OC)c(OC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (5.27 g, 54.0 mmol) and iPr2NEt (9.40 mL, 54.0 mmol) in CH2Cl2 (60 mL) was added AlMe3 (1.8 M solution in toluene, 30.0 mL, 54.0 mmol) dropwise at 0° C. After stirring at 0° C. for 1 h, a solution of methyl 1-[2-(difluoromethoxy)phenyl]-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (5:87 g, 17.99 mmol) in CH2Cl2 (60 mL) was added dropwise, and the mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with hexane/AcOEt (3/1) to give the title compound (4.79 g, 75% yield) as pale yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 3.38 (3H, s), 3.68 (3H, s), 3.89 (3H, s), 6.52 (1H, t, J=72.6 Hz), 7.37 (2H, m), 7.46-7.53 (1H, m), 7.62 (1H, dd, J=7.8, 1.5 Hz), 7.76 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][O:16][CH3:17])[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:9][C:3]=1[C:4](OCC)=[O:5].[CH:23]([O-])([O-])OC.C([O-])(=O)C.[NH4+:32]>CO>[CH3:22][O:21][CH2:20][CH2:19][O:18][C:10]1[CH:9]=[C:3]2[C:2](=[CH:12][C:11]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:1]=[CH:23][NH:32][C:4]2=[O:5]
Reactant: COC([O-])[O-]
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: COCCOc1cc2nc[nH]c(=O)c2cc1OCCOC
Temperature: 60 °C
Yield: 91.3 %

Procedure:
In a 20 L-volume glass reaction vessel equipped with a stirrer, a thermometer and a reflux condenser, 1,600 g (5.11 moles) of the ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate prepared in the Synthesis Example 3, 1,626 g (15.3 moles) of methyl orthoformate, 1,181 g (15.3 moles) of ammonium acetate and 4,800 mL of methanol were placed. The mixture was allowed to react under refluxing conditions (60 to 70° C.) for 7 hours while stirring. After the reaction was complete, the reaction solution was cooled to 60° C. To the reaction solution, 4,800 mL of methanol was added. The mixture was stirred for 30 minutes while maintaining the temperature, cooled to 0 to 5° C., and further stirred for 1 hour. The resulting mixture was filtered to obtain 1,373 g of 6,7-bis(2-methoxyethoxy)quinazolin-4-one as white crystals (isolation yield: 91%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1>C(O)C.C(O)(=O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccccn2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccccn2)CC1
Yield: 100 %

Procedure:
Tert-butyl 4-(pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.150 g, 0.576 mmol) was dissolved in ethanol (2 mL) and acetic acid (0.2 mL). The reaction mixture was hydrogenated with Pd/C (10%) in an H-cubemapparatus at about 60° C. for about 3 minutes. The solvent was removed in vacuo to give tert-butyl 4-(pyridin-2-yl)piperidine-1-carboxylate (0.151 g, 0.576 mmol) as white solid which was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method b) Rt 1.97 min; m/z: (M+H)+ 263.