Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][C:39](O)=[O:40])=[CH:37][C:32]=2[O:31][CH2:30]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][C:39](=[O:40])[CH2:38][C:36]3[CH:35]=[CH:34][C:33]4[O:29][CH2:30][O:31][C:32]=4[CH:37]=3)[N:13]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN)cc1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CNC(=O)Cc2ccc3c(c2)OCO3)cc1
Reaction time: 16 h
Yield: 64 %

Procedure:
To a mixture of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (300 mg, 0.74 mmol), benzo[1,3]dioxol-5-yl-acetic acid (134 mg, 0.74 mmol), 1-hydroxybenzotriazole hydrate (111 mg, 0.82 mmol), and N,N-diisopropyl-ethylamine (258 μL, 1.48 mmol) in acetonitrile (5 ml) at room temperature was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (157 mg, 0.82 mmol). The reaction mixture was stirred for 16 hours and the solvent evaporated in vacuo. The residue was taken into ethylacetate (50 ml), washed with water, 1 N hydrochloric acid, saturated sodium bicarbonate, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected to flash chromatography using a gradient of 10-20% ethylacetate/hexanes as eluent, which afforded 268 mg (64%) of 2-amino-5-((2-benzo[1,3]dioxol-5-yl-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][S:6](=[O:14])(=[O:13])[C:5]=2[S:4][C:3]=1[C:15]([OH:17])=[O:16].C(Cl)(=O)C(Cl)=O.[C:24]1(=O)[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][S:6](=[O:13])(=[O:14])[C:5]=2[S:4][C:3]=1[C:15]([O:17][C:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH:25]=1)=[O:16]
Reactant: Cc1c(C(=O)O)sc2c1C(C)(C)CCS2(=O)=O
Reactant: O=C1CCCC(=O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)OC2=CC(=O)CCC2)sc2c1C(C)(C)CCS2(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
2.0 g (0.0073 mol) of the title compound of Step D was added to 50 mL of methylene chloride. 1.27 mL (0.0146 mol) of oxalyl chloride (purchased from Janssen) was added followed by 2 drops of N,N-dimethylformamide. The mixture was refluxed under nitrogen for 2 h and then was evaporated to dryness. 50 mL of methylene chloride was added to the residue and then evaporated to dryness. Another 50 mL of methylene chloride was added to the residue and the solution was cooled to about 0° C. 0.90 g (0.0080 mol) of 1,3-cyclohexanedione (purchased from Aldrich Chemical Company) was added followed by 2.8 mL (0.020 mol) of triethylamine, and the mixture was stirred overnight while warming to room temperature. The mixture was evaporated to dryness, the residue was stirred in 100 mL of water and filtered. The crude product was washed with hexane to yield 2.32 g of the title compound of Step E as a solid melting at 133°-134° C. 1H NMR (CDCl3): δ 1.48 (s,6H), 2.1 (m,2H), 2.4 (m,4H), 2.6 (m,2H), 2.7 (s,3H), 3.4 (m,2H), 6.06 (s,1H).
Reaction SMILES: [NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(#N)C.CN1C(=O)CCC1>[CH3:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:3]2[C:2]=1[N:1]=[CH:20][N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[C:4]2=[O:5]
Reactant: COC(OC)OC
Reactant: Cc1cccc(C(=O)NC2CCC(=O)NC2=O)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cccc2c(=O)n(C3CCC(=O)NC3=O)cnc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72 %

Procedure:
A stirred solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-3-methyl-benzamide (0.9 g, 3.4 mmol) and trimethyl orthoformate (4.5 mL) and p-toluene sulfonic acid (250 mg) in acetonitrile (20 mL) was heated to reflux for 17 hours. To the mixture, was added water (75 mL) and stirred for 20 minutes. The suspension was filtered and washed with methanol (20 mL), water (20 mL) and ethyl acetate (20 mL) to give a purple solid. The solid in NMP (4 mL) was heated at 80° C. for 30 minutes. To the solution, was added water (1 mL), and the mixture was allowed to cool to room temperature. The suspension was filtered and washed with water (30 mL) to give 3-(8-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a light purple solid (660 mg, 72% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 3.07 min (98.6%); mp: 290-292° C.; 1H NMR (DMSO-d6) δ2.11-2.19 (m, 1H, CHH), 2.56 (s, 3H, CH3), 2.62-2.93 (m, 3H, CH2, CHH), 5.48 (br, 1H, NCH), 7.46 (t, J=8 Hz, 1H, Ar), 7.73 (d, J=8 Hz, 1H, Ar), 7.99 (d, J=8 Hz, 1H, Ar), 8.38 (s, 1H, CH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) δ 17.01, 22.53, 30.97, 56.22, 121.36, 123.79, 126.51, 126.86, 135.03, 135.47, 136.39, 145.96, 146.36, 159.97, 169.92, 172.52; LCMS: MH=272; Anal Calcd for C14H13N3O3: C, 61.99; H, 4.83; N, 15.49. Found: C, 61.70; H, 4.68; N, 15.40.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[NH:4][N:3]=1.C(SCCSCCSC1N=C2N(N=1)[C:38]([OH:41])=[CH:37][C:36]([CH3:42])=N2)CCCCC>>[CH2:11]([S:10][CH2:9][CH2:8][S:7][C:5]1[N:6]=[C:2]2[N:3]([N:4]=1)[C:38]([OH:41])=[CH:37][C:36]([CH3:42])=[N:1]2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCSCCSc1nc(N)n[nH]1
Reactant: CCCCCCSCCSCCSc1nc2nc(C)cc(O)n2n1
Product: CCCCCCCCSCCSc1nc2nc(C)cc(O)n2n1

Procedure:
Compound 14 was prepared from Compound 7 using a procedure analogous to that described previously for Compound 20. Recrystallization of the crude product from ethyl acetate gave a 59% yield of a white solid, m.p. 125.5°-127° C. Analysis: Calculated for C16H26N4OS2 : C,54.21; H, 7.39; N, 15.80. Found: C, 53.51; H, 7.21; N, 15.72.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([SH:12])[N:6]=[C:5]2[OH:13].CI.[O-][CH2:17]C.[Na+].Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([S:12][CH3:17])[N:6]=[C:5]2[OH:13]
Reactant: Oc1nc(S)nc2ccc(Br)cc12
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nc(O)c2cc(Br)ccc2n1

Procedure:
A solution of 6-bromo-2-mercapto-quinazolin-4-ol (0.32 g, 1.26 mmol), methyl iodide and sodium ethoxide in DMF (5 mL) was stirred at room temperature for 3 hours. HCl (1N, 3 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated to provide 0.31 g of crude product which was used without further purification. The product was characterized as follows: MS (m/z) 271 [M+H]+; HPLC retention time (Rt)=1.87 minutes (Method B).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[N:18](S(C3C=CC=CC=3)(=O)=O)[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].[Cl-].[NH4+]>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([S:14]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)(=[O:15])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-tert-butoxycarbonyl-4-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]piperazine (4.84 g), a 0.5N methanol solution of sodium hydroxide (20 ml) was added, followed by stirring at room temperature for 1 hour. Under ice cooling, a saturated aqueous solution of ammonium chloride was added to the reaction mixture. Water and dichloromethane were then added to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (methanol:dichloromethane=1:20), whereby the title compound (3.33 g, 93%) was obtained as colorless powder.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:67]([C:69]1[CH:83]=[CH:82][C:72]([CH2:73][NH:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[CH:71][CH:70]=1)=O>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:67]([C:69]3[CH:83]=[CH:82][C:72]([CH2:73][NH:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:78])[CH3:79])=[CH:71][CH:70]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 18 h
Yield: 65 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (200 mg, 0.51 mmol), DMF (2.55 mL), ethanol (0.45 mL), 1M Na2S2O4 (3 eq, 1.53 mmol, 1.53 mL) and tert-butyl N-(4-formylbenzyl)carbamate (1.1 eq, 0.21 mmol, 46 mg). After 18 h, filtration of the precipitate and washing with cold water (1 mL) gave the product (79 mg, 27%) as a colourless solid; 1H-NMR (500 MHz, DMSO-d6) 1.41 (s, 9H, C(CH3)3), 2.63-2.76 (m, 2H, piperazine NCH2), 2.89 (s, 2H, piperazine NCH2), 3.71-3.77 (m, 6H, piperazine N(CH2)2 & NCH2Ar), 4.19 (d, J=5.8 Hz, 2H, CH2NH—BOC), 7.39 (d, J=8.1 Hz, 2H, phenyl H-2 & H-6), 7.40-7.44 (m, 1H, pyridine H-5), 7.82 (s, br, 1H, pyridine H-4), 7.95 (s, br, 1H, NH—BOC), 8.12 (d, J=8.1 Hz, 2H, phenyl H-3 & H-5), 8.25 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.53 (br s, 1H, pyridine H-6), 8.60 (s, br, 1H, pyridine H-2), 13.49 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].Cl.[CH:8]([CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1)([CH3:10])[CH3:9].[OH2:23]>>[C:1]([OH:2])(=[O:4])[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:23].[CH:8]([CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1)([CH3:10])[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: O
Agent: COc1ccc2c(c1)CCNC2C(C)C
Agent: Cl
Agent: [K+]
Product: O=C(O)C(O)c1ccccc1
Temperature: 95 °C

Procedure:
Potassium carbonate (92 g) and water (500 mL) were added to 1-isopropyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (86 g). The reaction mixture was extracted with EtOAc and dried over magnesium sulfate, and then the solvent was evaporated. To the resulting residue were added iPrOH (1100 mL) and (+)-mandelic acid (50 g), followed by stirring under heating at 95° C. for dissolution. The mixture was left to cool and stirred at room temperature overnight. The resulting solid was collected and repeatedly recrystallized three times using iPrOH to obtain 1-isopropyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (+)-mandelate (43 g) as a single enantiomer.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([OH:18])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:9]=1>CO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([OH:18])=[C:8]([CH:10]([OH:11])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(Br)cc1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
1.02 g (27 mmol, 3.9 eqv) NaBH4 was added cautiously at rt to a solution of 1.92 g (6.9 mmol) (5-Bromo-2-hydroxy-phenyl)-phenyl-methanone (18) in 70 ml dry MeOH. After stirring this solution for 2 h at rt the solvent was evaporated and the residue was taken up in 70 ml water and 70 ml Et2O. The aq. layer was extracted with Et2O and the comb. org. fractions were washed twice with water, dried over Na2SO4 and evaporated. Column chromatography (Hexanes/EtOAc (1+1)) yielded 1.88 g (6.7 mmol, 98%) 19 as a white solid: Rf (Hexanes/EtOAc (1+1)) 0.57; mp 96-97° C.; 1H NMR (500 MHz, CDCl3) δ 2.76 (d, 1H, J=3.15 Hz), 5.98 (d, 1H, J=3.00 Hz), 6.79 (d, 1H, J=8.67 Hz), 6.98 (dd, 1H, J1=2.21 Hz, J2=0.47 Hz), 7.28 (dd, 1H, J1=8.67 Hz, J2=2.36 Hz), 7.33-7.41 (m, 5H), 7.92 (s, 1H); LRMS (EI) m/z 278 (5), 276 (4), 262 (56), 261 (100), 260 (46), 259 (95), 181 (21), 180 (12), 153 (12), 152 (33), 77 (16), 76 (16), 63 (10); HRMS (EI) Calcd. for C13H11BrO2: 277.994241. Found: 277.993366.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[C@H:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].Cl[CH2:33][CH2:34][CH2:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38](C)[C:37]1=[O:46].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:33][CH2:34][CH2:35][N:36]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:38][C:37]3=[O:46])[CH2:10][CH2:11]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[C@H:18]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20]
Reactant: CC1C(=O)N(CCCCl)c2ccccc21
Reactant: CC(C)(C)OC(=O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCNCC2)C1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCN3C(=O)Cc4ccccc43)CC2)C1=O
Temperature: 81 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
A mixture of (R)-tert-butyl 2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (250 mg, 0.60 mmol, 1 equiv), 1-(3-chloropropyl)-3-methylindolin-2-one (125.8 mg, 0.60 mmol, 1 equiv), sodium iodide (36 mg, 0.24 mmol, 0.4 equiv), and potassium carbonate (166 mg, 1.2 mmol, 2 equiv) in 2-butanone was stirred at 81° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using preparative thin layer chromatography in 10% methanol in dichloromethane to afford the title compound as a cream solid (100 mg, 28%); MS for C36H42N4O4 m/z 595.32 (M+H)+.
Reaction SMILES: [CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH3:7][N+:8]([CH3:23])([CH3:22])[CH2:9][CH2:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O>O.[Pd]>[CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]([CH3:21])[CH2:10][CH2:9][N+:8]([CH3:23])([CH3:22])[CH3:7]
Reactant: CN(CC[N+](C)(C)C)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: COS(=O)(=O)[O-]
Solvent: O
Product: CN(CC[N+](C)(C)C)c1ccccc1N

Procedure:
4.5 g (12.9 mmol) of the compound from Step 10.3 was dissolved in 80 mL of water and hydrogenated for 2 hours in the presence of 0.3 g of Pd/C (10%) under a hydrogen pressure of 9 bar. The catalyst was then filtered off, and the filtrate was evaporated to dryness. This gave 4.1 g (99% of the theoretical) of a violetish oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[N:4][C:5]([F:11])=[C:6]([Cl:10])[C:7]=1[CH2:8][OH:9].[Cl:13][C:14]([C:24]([F:27])([F:26])[F:25])=[CH:15][C@@H:16]1[C@H:18]([C:19](Cl)=[O:20])[C:17]1([CH3:23])[CH3:22]>>[Cl:13][C:14]([C:24]([F:25])([F:26])[F:27])=[CH:15][C@@H:16]1[C@H:18]([C:19]([O:9][CH2:8][C:7]2[C:2]([Cl:1])=[C:3]([F:12])[N:4]=[C:5]([F:11])[C:6]=2[Cl:10])=[O:20])[C:17]1([CH3:23])[CH3:22]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: OCc1c(Cl)c(F)nc(F)c1Cl
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OCc1c(Cl)c(F)nc(F)c1Cl

Procedure:
By The method of Example 2, 0.6 (0.002 mole) of 3,5-dichloro2,6-difluoro-4-hydroxymethylpyridine (Example 15) was reacted with 0.61 g (0.002 mole) of cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarbonyl chloride to produce, after purification using the Chromatotron, 0.5 g of (3,5-dichloro-2,6-difluoropyridin-4-yl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate as a clear, white liquid, compound 21 in the Tables below.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[CH2:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].O.C(OCC)(=O)C>[CH3:9][C:10]1[CH:11]=[C:12](/[CH:13]=[CH:14]/[C:2]2[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][CH:8]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1cccc(Br)c1
Reactant: C=Cc1cccc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cccc(/C=C/c2cccc(N)c2)c1
Temperature: 100 °C

Procedure:
A mixture of 3-bromoaniline (545 uL), 3-methylstyrene (780 uL), tri(o-tolyl)phosphine (60 mg), Pd(OAc)2 (10 rag), and triethylamine (2.5 mL) was prepared in a sealed tube under argon atmosphere. The reaction was heated at 100° C. for 4 h, then cooled to room temperature and poured into ethyl acetate and water. The organic layer was washed with water and dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Purification by silica gel chromatography (20:1-5:1 hexane/EtOAc) provided the titled compound.
Reaction SMILES: [CH2:1]([O:7]C1C=CC=C2C(NC(=O)C=12)=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C([NH2:23])CCC.C(OCC)C.[ClH:29]>C(O)C>[ClH:29].[CH2:1]([O:7][NH2:23])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2c(OCc3ccco3)cccc21
Reactant: CCCCN
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: NOCc1ccco1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.28 g of [-furfuryloxyphthalimide [prepared as described in step (i) above] were dissolved in 20 ml of ethanol, and 1.37 g of butylamine were added to the resulting solution. The mixture was then stirred for 1 hour at room temperature, after which diethyl ether was added. The mixture was then acidified by the addition of a 10% by volume methanolic solution of hydrogen chloride, and the resulting crystals were collected by filtration, to afford 2.62 g of the title compound. Nuclear Magnetic Resonance Spectrum (CD3OD, 270 MHz), δ ppm: 5.07 (2H, singlet); 6.54 (1H, doublet of doublets, J=2 & 3 Hz); 6.72 (1H, doublet, J=3 Hz); 7.67 (1H, doublet, J=2 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[C:29]([CH3:30])=[C:28]([O:31][CH3:32])[CH:27]=[CH:26][C:20]=1[CH:21]=[CH:22][C:23](O)=O>>[CH3:17][O:18][C:19]1[C:29]([CH3:30])=[C:28]([O:31][CH3:32])[CH:27]=[CH:26][C:20]=1/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1C
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(C)c3OC)nc2n(CCC)c1=O
Yield: 50.1 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 1.25 g (5.52 mmol) of 5,6-diamino-1,3-dipropyluracil and 1.35 g (6.08 mmol) of 2,4 -dimethoxy-3-methylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.14 g (yield 50%) of Compound 14 as white needles.
Reaction SMILES: N#N.[F:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH:10]=2)=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>C1COCC1>[F:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[N:13]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH:10]=2)=[CH:6][CH:5]=1
Reactant: Fc1ccc(Cc2cc(-c3ccncc3)n[nH]2)cc1
Reactant: COC(=O)CBr
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
A 22 liter, three-neck, round bottom flask equipped with a mechanical stirrer, Claisen adapter with a thermocouple and N2 inlet adapter, and a 250 ml addition funnel was charged with THF (10 L), and 4-[5-(4-fluorobenzyl)-1H-pyrazol-3-yl]pyridine (385.5 g, 1.52 mol). The resulting solution was cooled to 5° C. using a water/ice/salt bath. Sodium hydride (60% dispersion in mineral oil, 66.9 g, 1.67 mol) was then added in several portions at such that the internal temperature did not exceed 15° C. The resulting red mixture was stirred at 5° C. for 1.5 hours. Methyl bromoacetate (254 g, 1.67 mol) was then added drop-wise at such a rate that the temperature did not exceed 15° C. The mixture was then allowed to slowly reach room temperature overnight. The mixture was then filtered through celite, and the celite was washed with ethyl acetate. The majority of the THF was removed by rotary evaporation. Ethyl acetate (4 L) and water (4 L) were then added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×3 L). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The mixture of isomers (80:20 by GC-MS) was then eluted through silica gel using 100% ethyl acetate. The fractions that contained the isomers were concentrated and the solid suspended in ether (3 L). After heating to boiling, ethyl acetate (2 L) was added until the solid dissolved, followed by hexanes (4 L). After cooling overnight, the solid was filtered and dried under reduced vacuum to give the title compound as a red solid (235 g, 47%). 1H NMR (400 MHz, CD2Cl2) δ ppm 8.56 (d, 2 H) 7.61 (d, 2 H) 7.20 (t, 2 H) 7.03 (t, 2 H) 6.42 (s, 1 H) 4.86 (s, 2 H) 3.96 (s, 2 H) 3.71 (s, 3 H); m/z (APCI+) for C18H16N3O2F 326.1 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][OH:13])[CH:6]=1)=[O:4].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:33]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)=[CH:6][C:7]=1[CH2:12][OH:13]
Reactant: c1ccc(CNCCCCCCOCCCCCCc2ccccn2)cc1
Reactant: O=C(CBr)c1ccc(O)c(CO)c1
Solvent: C1CCOC1
Product: O=C(CN(CCCCCCOCCCCCCc1ccccn1)Cc1ccccc1)c1ccc(O)c(CO)c1
Reaction time: 24 h
Yield: 90.4 %

Procedure:
A solution of 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (1.00 g), N-[6-[[6-(2-pyridinyl)hexy]oxy]hexyl]benzenemethanamine (1.5 g) and DEA (1.58 g) in THF (20 ml) was left to stand for 24 h. The reaction mixture was filtered and the filtrate was concentrated to give an oil which was purified by FCC eluting with System B (95:5:1), to give the title compound as a yellow oil (1.96 g), t.l.c. (System A 80:20:2)) Rf 0.33.