Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB([C:32]2[CH2:33][CH2:34][O:35][CH2:36][CH:37]=2)O1>O1CCOCC1>[O:35]1[CH2:34][CH:33]=[C:32]([C:2]2[CH:3]=[C:4]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH2:37][CH2:36]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(Br)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN1CCN(c2ccc([N+](=O)[O-])c(C3=CCOCC3)c2)CC1
Temperature: 25 °C
Yield: 36 %

Procedure:
1-(3-Bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared in Example 9, step (a)) (225.1 mg, 0.79 mmol), K2CO3 (310.9 mg, 2.25 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (Murata, M., et al, Synthesis, 778, (2000)) (157 mg, 0.75 mmol) in dioxane (5 mL) was heated at 80° C. overnight under Ar. The reaction mixture was allowed to cool to RT, concentrated, and the resulting residue was chromatographed on silica (10% EtOAc/hexane-20% MeOH/EtOAc) to obtain the title compound (82 mg, 36%). 1H-NMR (CDCl3; 400 MHz): δ 8.04 (d, 1H, J=9.4 Hz), 6.78 (dd, 1H, J=9.4, 2.6 Hz), 6.58 (m, 1H, J=2.6 Hz), 5.58 (m, 1H), 4.34 (m, 2H), 3.95 (t, 2H, J=5.3 Hz), 3.46 (m, 4H), 2.57 (m, 4H), 2.38 (s, 3H), 2.30 (m, 2H).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:40])[CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:37]=[CH:38][CH:39]=1)[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32](O)=[O:33])=[CH:29][CH:30]=2)[C:25]([CH3:35])=[C:24]1[CH3:36]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:32]([C:28]2[CH:27]=[C:26]3[C:31](=[CH:30][CH:29]=2)[N:23]([CH2:22][C:21]2[CH:20]=[C:19]([CH:39]=[CH:38][CH:37]=2)[O:18][CH2:17][C:16]([O:15][CH3:14])=[O:40])[C:24]([CH3:36])=[C:25]3[CH3:35])=[O:33])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)COc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)COc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the 1-(3-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1>>[B:8]([C:5]1[CH:4]=[N:3][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([OH:19])=[O:18])[CH2:12]2)=[N:7][CH:6]=1)([OH:10])[OH:9]
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: O=C(O)[C@@H]1CCCNC1
Product: O=C(O)[C@@H]1CCCN(c2ncc(B(O)O)cn2)C1

Procedure:
The title compound was synthesised from (2-chloropyrimidin-5-yl)boronic acid and (3R)-piperidine-3-carboxylic acid in accordance with General Method C.
Reaction SMILES: [F:1][C:2]([F:30])=[C:3]([F:29])[C:4]([F:28])([F:27])[O:5][C:6]([F:26])([F:25])[C:7]([F:24])([F:23])[C:8]([F:22])([F:21])[O:9][C:10]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:11]=1[F:20].[O:31]=O>>[F:30][C:2]1([F:1])[O:31][C:3]1([F:29])[C:4]([F:27])([F:28])[O:5][C:6]([F:26])([F:25])[C:7]([F:23])([F:24])[C:8]([F:21])([F:22])[O:9][C:10]1[C:11]([F:20])=[C:12]([F:19])[C:13]([F:18])=[C:14]([F:17])[C:15]=1[F:16]
Reactant: FC(F)=C(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=O
Product: Fc1c(F)c(F)c(OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C2(F)OC2(F)F)c(F)c1F
Yield: 31 %

Procedure:
A 100-ml metal tube lined with stainless steel and charged with 105.3 g (0.22 mol) of perfluoro(7-phenoxy-4-oxa-1-heptene) was heated at 140° while oxygen was pressured in intermittently until no pressure drop was observed. The liquid product mixture was fractionated to afford 78.5 g of distillate, bp 37°-70° (3 min). The distillation was shaken with 1 liter of ice water, and then 25 ml of CFCl2CF2Cl and some calcium sulfate were added to hasten separation. The lower layer was dried over calcium sulfate and fractionated to give 33.3 g (31%) of perfluoro(7-phenoxy-1,2-epoxy-4-oxaheptane), bp 55° (1.9 mm). IR (CCl4): 6.47 (epoxide ring), 6.58 (aromatic C=C), 8-9μ (CF, C-O). NMR (CCl4): 19F -84.1 (m, 2F, OCF2), -84.6 (m, 2F, OCF2), -129.0 (s, 2F, CF2), -151.8 (m, 2F, arom. CF), -155.1 (t, JFF 21.0 Hz, 1F, arom. CF), -156.6 (t, JFF 17.9 (Hz, ring CF), and -161.7 ppm (m, 2F, arom. CF), with AB groupings at -7382, -7534, -7566, and -7719 Hz (m, 2F) for CF2 adjacent to epoxide ring and at -10381 and -10424 Hz (d of t, JFF 18.8, 9.8 Hz, 1F) and -10600 and -10642 Hz (d, JFF 17.3 Hz, 1F) for epoxide CF2.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][Cl:27]>CC(C)=O>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccccc1)c1ccc(OCCCCCl)cc1
Reaction time: 20 h

Procedure:
Combine 4-hydroxybenzophenone (8 kg, 57,6 mol), potassium carbonate (8 kg, 57.6 mol), and 1-bromo-4-chlorobutane (8.384 kg, 48.9 mol) in acetone (40 L). Heat to reflux. After 20 hours, cool the reaction mixture and filter. Rinse the filter cake with acetone and evaporate the filtrate in vacuo to obtain 4-(4-chlorobutoxy) benzophenone.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: O=C(N[C@@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: CC(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A142) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][N:13]2[C:17]3=[N:18][C:19]([C:22](=O)[CH3:23])=[CH:20][N:21]=[C:16]3[N:15]=[N:14]2)=[C:10]([F:25])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[NH2:27][O:28][CH2:29][CH2:30][OH:31]>CO>[OH:31][CH2:30][CH2:29][O:28]/[N:27]=[C:22](/[C:19]1[N:18]=[C:17]2[N:13]([CH2:12][C:11]3[C:2]([F:1])=[C:3]4[C:8](=[CH:9][C:10]=3[F:25])[N:7]=[CH:6][CH:5]=[CH:4]4)[N:14]=[N:15][C:16]2=[N:21][CH:20]=1)\[CH3:23]
Reactant: NOCCO
Reactant: CC(=O)c1cnc2nnn(Cc3c(F)cc4ncccc4c3F)c2n1
Agent: Cl
Solvent: CO
Product: C/C(=N\OCCO)c1cnc2nnn(Cc3c(F)cc4ncccc4c3F)c2n1
Temperature: 50 °C
Yield: 60.1 %

Procedure:
To a solution of 1-(1-((5,7-difluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (3.5 mg, 0.01 mmol) in MeOH (1 mL), 2-(aminooxy)ethanol hydrochloride (intermediate S) (1.6 mg, 0.02 mmol) was added, the solution was heated to 50° C. for overnight. The solvent was removed in vacuo. The residue was diluted with water, treated with aqueous NaHCO3 solution, extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prepared HPLC to give white solid (E)-1-(1-((5,7-difluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-2-hydroxyethyl oxime (2.4 mg, 56%). 1H-NMR (400 MHz, CDCl3) δ ppm 9.38 (s, 1H), 8.98 (d, 1H), 8.42 (d, 1H), 7.64 (d, 1H), 7.48 (m, 1H), 6.18 (s, 2H), 4.45 (m, 2H), 3.98 (m, 2H), 2.36 (s, 3H), 1.96 (m, 1H). LCMS (method B): [MH]+=399.9, tR=2.19 min.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[N:11]=[N:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1>ClCCl>[Cl:3][CH2:19][CH2:18][CH:15]1[CH2:16][CH2:17][N:12]([C:9]2[N:10]=[N:11][C:6]([CH3:5])=[CH:7][CH:8]=2)[CH2:13][CH2:14]1
Reactant: Cc1ccc(N2CCC(CCO)CC2)nn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(N2CCC(CCCl)CC2)nn1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred and cooled (ice bath) solution of 7.1 parts of thionyl chloride in 65 parts of dichloromethane was added dropwise a solution of 6.6 parts of 1-(6-methyl-3-pyridazinyl)-4-piperidineethanol in 195 parts of dichloromethane. Upon complete addition, stirring was continued overnight at room temperature. The reaction mixture was washed with alkaline water. The separated organic layer was dried, filtered and evaporated, yielding 7.2 parts (100%) of 3-[4-(2-chloroethyl)-1-piperidinyl]-6-methylpyridazine as a residue (int. 84).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]2[CH:15]=1)=[O:4].[I:18]N1C(=O)CCC1=O.O>C(#N)C>[F:17][C:2]([F:16])([F:1])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]2[C:15]=1[I:18])=[O:4]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(Nc1cn2cc(F)ccc2n1)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: O=C(Nc1nc2ccc(F)cn2c1I)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,2,2-trifluoro-N-(6-fluoroimidazo[1,2-a]pyridin-2-yl)acetamide (0.89 g, 0.0036 mol) was dissolved in acetonitrile (20 mL) and was cooled at 0° C. N-Iodosuccinimide (0.89 g, 0.0040 mol) was added and the reaction was stirred for 30 minutes. The mixture was poured into water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organics were dried with magnesium sulfate and the solvent removed. The residue was chromatographed on silica (60% ethyl acetate/hexanes) to give 2,2,2-trifluoro-N-(6-fluoro-3-iodoimidazo[1,2-a]pyridin-2-yl)acetamide 4 Rf 0.40, 60% ethyl acetate/hexanes; MS m/z 374 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:13](=[O:17])[C@H:14]([OH:16])[CH2:15][C:4]=2[CH:3]=1.C1COCC1.[H-].[Na+].[O:30]=[C:31]1[C:40]([CH:41]2[CH2:46][CH2:45][N:44]([C:47](OC3C=CC([N+]([O-])=O)=CC=3)=[O:48])[CH2:43][CH2:42]2)=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32]1>>[O:30]=[C:31]1[C:40]([CH:41]2[CH2:42][CH2:43][N:44]([C:47]([O:16][C@H:14]3[C:13](=[O:17])[N:12]([CH2:18][C:19]([F:21])([F:20])[F:22])[CH2:11][C:5]4[C:6]5[CH:7]=[N:8][NH:9][C:10]=5[C:2]([Cl:1])=[CH:3][C:4]=4[CH2:15]3)=[O:48])[CH2:45][CH2:46]2)=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Reactant: O=C1[C@H](O)Cc2cc(Cl)c3[nH]ncc3c2CN1CC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Reaction time: 48 h
Yield: 36.1 %

Procedure:
(R)-4-chloro-7-hydroxy-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one (60.0 mg, 0.180 mmol) in THF (10.0 mL, 122 mmol) was added sodium hydride (10.79 mg, 0.450 mmol) followed by 4-nitrophenyl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (106 mg, 0.270 mmol). After stirring for 48 h, most of the solvent was removed, diluted with dichloromethane (30 mL) and neutralized with 1.0 M HCl. The organic phase was separated, dried (Na2SO4) and the crude product was purified by flash chromatography using 5% MeOH in dichloromethane to give (R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (38.00 mg, 0.065 mmol, 36% yield). MS (ESI) 588 (M+H); Rf=2.73.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:11]1([O-:22])[C:16]([Cl:17])=[C:15]([Cl:18])[C:14]([Cl:19])=[C:13]([Cl:20])[C:12]=1[Cl:21].[Na+].O.C(O)C>C(O)C>[Cl:17][C:16]1[C:15]([Cl:18])=[C:14]([Cl:19])[C:13]([Cl:20])=[C:12]([Cl:21])[C:11]=1[O:22][CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [O-]c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: ClCC=Cc1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1c(Cl)c(Cl)c(OCC=Cc2ccccc2)c(Cl)c1Cl
Yield: 85 %

Procedure:
In a 500 ml four necked flask equipped with a stirrer, a thermometer and a nitrogen gas inlet, chloromethylstyrene (m/p=60/40) (25 g, 0.161 mole) was dissolved in ethanol (50 ml) at room temperature. A solution of sodium pentachlorophenate (hereinafter abbreviated as Na-PCP) (49 g. 0.170 mole) in a mixed solvent of water/ethanol (1/1, 250 ml) was gradually added dropwise thereto and, after completion of addition, the mixture was reacted at 50° C. for 1 hour. The mixture was cooled and the resulting precipitate was filtered off. The filtrate was concentrated with a rotary evaporator. Then, n-hexane (250 ml) and distilled water (100 ml) were added to the concentrated solution and the mixture was shaken. The aqueous layer was removed and additional distilled water (100 ml) was added. This procedure was repeated to remove unreacted Na-PCP. The hexane layer was evaporated with a rotary evaporator. Then, the solid residue was recrystallized from acetone to obtain (2, 3, 4, 5, 6-pentachlorophenyloxy)methylstyrene of the formula [Ia] as white needle crystals, m.p. 113°-115° C., yield 85%.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(=[O:5])[CH3:4].I[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[C:3]([O:6][CH2:7][C:8]([CH:9]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:17])(=[O:5])[CH3:4]
Reactant: CCOC(=O)CCI
Reactant: CC(=O)OCC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(C(=O)COC(C)=O)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
To a suspension of 60% NaH (1.02 g) in THF (50 mL) was added tert-butyl 4-(acetyloxy)-3-oxobutanoate (5.00 g) under ice-water cooling and the mixture was stirred at 0° C. for 0.5 hour. To this added ethyl 3-iodopropanoate (5.54 g) and the mixture was stirred at 50° C. for 8 hours. The mixture was partitioned between AcOEt and water. The organic layer was separated, washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-3:1) to give 1-tert-butyl 5-ethyl 2-[(acetyloxy)acetyl]pentanedioate as yellow oil (4.27 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][OH:21])[CH2:14][CH2:13]3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:34]=[C:35]=[O:36])[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31]>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:34][C:35]([O:21][CH2:20][CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[CH2:13][CH2:14]2)=[O:36])[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31]
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Reactant: Cn1nc(C2CCN(CCCO)CC2)c2ccc(F)cc21
Product: COc1cc(NC(=O)OCCCN2CCC(c3nn(C)c4cc(F)ccc34)CC2)cc(OC)c1OC
Yield: 67.9 %

Procedure:
Starting from 4-(6-fluoro-1-methyl-1H-indazol-3-yl)-1-(3-hydroxyprop-1-yl)piperidine (300 mg, 1.03 mmol) and 3,4,5-trimethoxyphenylisocyanate (300 mg, 1.44 mmol) using the procedure described in example 1B was prepared 350 mg (68%) of the title compound. M.p. 85°-88° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Cl[CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: COc1ccccc1COCCCCl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Temperature: 120 °C
Reaction time: 60 h
Yield: 87.5 %

Procedure:
(α) A solution of 5.2 g (17.7 mmol) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate [Example 46(b)] and 3.37 ml (3.8 g,17.7 mmol) of 2-methoxybenzyl 3-chloropropyl ether in 18 ml of absolute DMF was treated with 3.7 g (26.9 mmol) of anhydrous potassium carbonate and stirred at 120° C. for 60 h. For the working-up, the reaction mixture was partitioned between 250 ml of water and 250 ml of ethyl acetate. The organic phase was separated and the aqueous phase was extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were washed twice with 100 ml of water each time and finally the solvent was distilled off under reduced pressure. The crude product was crystallized by treatment with ether. There were obtained 7.3 g (88% of theory) of tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 472 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:17][O:18][P:19]([O:22]C)[O:20][CH3:21]>>[CH3:17][O:18][P:19]([CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:22])[O:20][CH3:21]
Reactant: ClCc1c2ccccc2cc2ccccc12
Reactant: COP(OC)OC
Product: COP(=O)(Cc1c2ccccc2cc2ccccc12)OC
Yield: 40.5 %

Procedure:
A solution of 9-(chloromethyl)anthracene (2.5 g, 0.011M) in trimethylphosphite (5 mL, 5.26 g, 0.042 M) is heated at reflux temperature for 72 hours. Excess trimethylphosphite is removed under reduced pressure and the residue is chromatographed over silica gel (400 g, 40-63 μm, CH2Cl2, 50 mL fractions) using CH2Cl2 (60 fractions) and 2% CH3OH in CH2Cl2 for the remaining fractions. Fractions 86-93 (2.99 g) are found to contain desired material and an impurity and are rechromatographed (400 g silica gel, 40-63 lam, CH2Cl2, 50 mL fractions) using 2.5% acetone-CH2Cl2 to elute the column. Fractions 100-160 contains compound (1.495 g, 0.00498M, 45%) as a yellow solid. Crystallization from ethyl acetate gives the title compound (1.34 g) as yellow needles, mp 152°-153° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[C:38](Cl)=[O:39]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:38]([C:29]3[CH:30]=[CH:31][C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:28]=3)=[O:39])[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(NC2CCN(C(=O)c3ccc4ccccc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.5 %

Procedure:
Compound (49) (0.056 g, 0.2 mmol) and triethylamine (0.14 mL, 1 mmol) were added sequentially to a solution of 2-naphthoyl chloride (0.114 g, 0.6 mmol) in CH2Cl2 (5 mL) at 25° C. The mixture was stirred at 25° C. for 12 h, then was concentrated in vacuo to a residue. Purification of the residue by flash column chromatography (gradient elution 5 to 30% EtOAc in hexanes) provided the title compound (0.04 g, 50%): TLC (Rf =0.50; 50% EtOAc/hexanes); 1H NMR (CDCl3) δ 7.84 (m, 6H), 7.51 (m, 3H), 6.55 (d, 2H, J=8.8), 4.65 (br s, 1H), 4.01 (d, 2H, J=7.8), 3.66 (m, 1H), 3.18 (t, 2H, J=11.2), 2.05 (m, 2H), 1.56 (s, 9H), 1.46 (m, 2H); 13C NMR (CDCl3) δ 170.5, 166.0, 150.1, 133.8, 133.3, 132.9, 131.5, 128.4, 127.9, 127.8, 127.1, 126.8, 124.2, 121.1, 111.9, 79.9, 49.9, 32.6, 28.4; HRMS (FAB) m/z 430.2241 (M)+ (C27H30N2O3 requires 430.2256).
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Br:5][C:6]1[CH:11]=[CH:10][N+:9](O)=[C:8](C)[C:7]=1C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[CH:8][N:9]=[C:2]([CH2:1][OH:4])[C:11]=1[CH3:10]
Reactant: Cc1c(Br)cc[n+](O)c1C
Reactant: CC(=O)[O-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(Br)ccnc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To a stirred solution of 4-bromo-1-hydroxy-2,3-dimethyl-pyridin-1-ium acetate (which may be prepared as described in Description 5) (18120 mg, 69.13 mmol) in DCM (100 mL) was added trifluoroacetic anhydride (23.89 mL, 171.9 mmol) dropwise and the reaction was stirred at room temperature for 8 hours, then additional trifluoroacetic anhydride (23.89 mL, 171.9 mmol) was introduced. After 1 day, the reaction mixture was concentrated in vacuo to remove excess TFAA & DCM. The residue was then diluted with MeOH (200 mL) and a solution of saturated aqueous K2CO3 (approximately 100 mL) was added with caution [exotherms]. The resultant suspension was stirred for 3 hours and then concentrated in vacuo. The residue was then partitioned between DCM (200 mL) and water (200 mL). The organics were separated and dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and trifluoroacetic anhydride (23.89 mL, 171.9 mmol) was added dropwise and the reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, and the residue, diluted with MeOH (200 mL) and a solution of saturated aqueous K2CO3 (approximately 100 mL) was added with caution, and the resulting suspension was stirred for 3 hours. The reaction mixture was then concentrated in vacuo, and the residue was partitioned between DCM (200 mL) and water (200 mL). The organics were separated and dried over MgSO4, filtered and concentrated in vacuo. The residue was purified over silica (100 g SNAP), using the Isolera instrument, eluting with EtOAc: isohexane 0%-50%. Fractions containing desired product were combined and concentrated in vacuo to give (4-bromo-3-methyl-2-pyridyl)methanol (D6) (7055 mg, 34.917 mmol, 50.5% yield) as a yellow solid;
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: NCC1CCCCC1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(NCC2CCCCC2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[(cyclohexyl)methylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, aminomethylcyclohexane, and triethylamine essentially as described above in Example 1, Scheme A, step b.