Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:4][C:5]([C:8]2[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([F:15])[CH:9]=2)=[CH:6][N:7]=1.[CH2:24](B(O)O)[CH3:25].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:14][C:13]1[C:8]([C:5]2[N:4]=[C:3]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:2]([CH2:24][CH3:25])=[N:7][CH:6]=2)=[CH:9][C:10]([F:15])=[N:11][CH:12]=1
Reactant: CCB(O)O
Reactant: Fc1cc(-c2cnc(Cl)c(NCC3CCOCC3)n2)c(Cl)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: CCc1ncc(-c2cc(F)ncc2Cl)nc1NCC1CCOCC1
Temperature: 115 °C
Yield: 14.4 %

Procedure:
3-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (0.0347 g, 0.097 mmol), ethylboronic acid (0.014 g, 0.194 mmol), and sodium carbonate (0.126 ml g, 0.253 mmol, 2 M aq solution) were dissolved in DME (1 ml). The solution was then degassed by sparging with argon for 5 min. At this time it was treated with PdCl2(dppf).CH2Cl2 adduct (0.016 g, 0.019 mmol). The reaction mixture was then heated in the microwave at 115° C. for 25 min. More ethylboronic acid (0.014 g, 0.194 mmol) and PdCl2(dppf).CH2Cl2 adduct (0.016 g, 0.019 mmol) were added. The reaction mixture was then heated in the microwave at 115° C. for 25 min. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo to afford 0.0709 g of crude product. The material was purified using the Isco with a 4 g SiO2 column. The resulting residue was subjected to silica gel column chromatography. Elution using 20 EtOAc/80 heptane to 70 EtOAc/30 heptane gave 0.0049 g (14%) of 6-(5-chloro-2-fluoropyridin-4-yl)-3-ethyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2-amine. LCMS (m/z): 351.1 (MH+), retention time=0.97 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([F:27])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([O:19][CH3:20])[CH:13]=1)[CH:9]=[C:8]([C:21]([O:23]CC)=[O:22])[C:7]2=[O:26].Cl>C(O)(=O)C>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([F:27])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([O:19][CH3:20])[CH:13]=1)[CH:9]=[C:8]([C:21]([OH:23])=[O:22])[C:7]2=[O:26]
Reactant: CCOC(=O)c1cn(-c2ccc(F)c(OC)c2)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ccc1F
Yield: 94.2 %

Procedure:
Ethyl 8-chloro-6,7-difluoro-1-(4-fluoro-3-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (400 mg) was added to a mixed liquid (1:1, v/v; 2.5 ml) of 2N hydrochloric acid and acetic acid, and the mixture was stirred and heated under reflux for 2 hours. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (351 mg) as a colorless powder.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([NH2:14])[CH:6]=[C:7]([F:13])[C:8]=2[CH3:12])[C:3]1=[O:15].C(O)C.C([O:21][C:22](=O)[C:23]([F:26])([F:25])[F:24])C.Cl>C(N(CC)CC)C.C1COCC1>[NH2:14][C:5]1[CH:6]=[C:7]([F:13])[C:8]([CH3:12])=[C:9]2[C:4]=1[C:3](=[O:15])[CH:2]([NH:1][C:22](=[O:21])[C:23]([F:26])([F:25])[F:24])[CH2:11][CH2:10]2
Reactant: Cc1c(F)cc(N)c2c1CCC(N)C2=O
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(F)cc(N)c2c1CCC(NC(=O)C(F)(F)F)C2=O
Temperature: 20 °C
Reaction time: 20 h

Procedure:
The compound obtained in (8) above (1.66 gm) was dissolved into a mixed solvent of 70 ml of ethanol and 10 ml of THF. To the solution were added 2 ml of triethylamine and 1.5 ml of ethyltrifluoroacetate, followed by stirring for 20 hours at 20° C. The reaction product was added to dilute aqueous solution of hydrochloric acid and extracted with chloroform. The extract was washed with water, saturated sodium bicarbonate and saturated brine in this order, and dried over anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue was subjected to silica gel column chromatography using chloroform as an eluant to obtain fractions containing the target compound. The fractions were concentrated to obtain 1.79 gm of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.NC1C=C(Cl)C=CC=1CO.C(N(CC)CC)C.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29]>CN(C=O)C>[NH2:1][C:2]1[C:3](/[CH:29]=[CH:28]/[C:27]([O:31][CH3:32])=[O:30])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=CC(=O)OC
Reactant: Nc1cc(Cl)cnc1Br
Agent: Nc1cc(Cl)ccc1CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ncc(Cl)cc1N
Yield: 63.6 %

Procedure:
A solution of 3-amino-2-bromo-5-chloropyridine (2.257 ml, 19.96 mmol), Reactant 2 (0.283 g, 0.399 mmol), triethylamine (3.03 g, 29.9 mmol) and methyl acrylate (3.44 g, 39.9 mmol) in 5 mL of DMF was heated at 145° C. under microwave irradiation for 35 min. The reaction mixture was evaporated to dryness and was loaded to flash column (DCM to DCM/EA=10:1) to give 1.98 g of pure (E)-methyl 3-(3-amino-5-chloropyridin-2-yl)acrylate (2.7 g, 12.70 mmol, 63.6% yield) as a light yellow solid and 820 mg of less pure product. 1H NMR (400 MHz, chloroFORM-d) δ ppm=8.01 (d, J=1.8 Hz, 1 H), 7.72 (d, J=15.1 Hz, 1 H), 7.01 (d, J=2.0 Hz, 1 H), 6.92 (d, J=15.3 Hz, 1 H), 4.02 (br. s., 2 H), 3.81 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:34][CH2:35][CH3:36])[C:13]([C:15]1[CH:16]=[C:17]2[CH:23]=[CH:22][N:21]([Si](C(C)C)(C(C)C)C(C)C)[C:18]2=[N:19][CH:20]=1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+](C)(C)C.[F-]>C1COCC1.C([O-])(O)=O.[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:34][CH2:35][CH3:36])[C:13]([C:15]1[CH:16]=[C:17]2[CH:23]=[CH:22][NH:21][C:18]2=[N:19][CH:20]=1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC1(C(=O)c2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)CCCN1C(=O)OC(C)(C)C
Agent: C[N+](C)(C)C
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC1(C(=O)c2cnc3[nH]ccc3c2)CCCN1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a stirred solution of 2-propyl-2-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.415 g, 0.809 mmol) in THF (7.5 mL) at ambient temperature under nitrogen was added TMAF (0.753 g, 8.09 mmol). The reaction mixture was stirred for one hour, then diluted with saturated aqueous NaHCO3 (30 mL) and water (15 mL) and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to a pale yellow gum. Purification by chromatography (silica, 50 to 100% EtOAc in hexanes) gave 2-propyl-2-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.247 g, 0.692 mmol, 86%) as a colourless foam.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[Cl:8][C:9]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:10]=1[C:11]([NH:13][CH2:14][C:15]1([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[CH3:25])[CH2:18][NH:17][CH2:16]1)=[O:12].C(N(CC)CC)C.CN(C)CCN>ClCCl>[Cl:8][C:9]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:10]=1[C:11]([NH:13][CH2:14][C:15]1([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[CH3:25])[CH2:16][N:17]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[CH2:18]1)=[O:12]
Reactant: CN1CCCCC1C1(CNC(=O)c2c(F)ccc(F)c2Cl)CNC1
Reactant: CCCS(=O)(=O)Cl
Agent: CN(C)CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CC(CNC(=O)c2c(F)ccc(F)c2Cl)(C2CCCCN2C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-butyl 3-{[(2-chloro-3,6-difluorobenzoyl)amino]methyl}-3-(1-methylpiperidin-2-yl)azetidine-1-carboxylate (0.40 g, 0.9 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (2 eq) was added. The reaction was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue treated with saturated aqueous sodium carbonate. The product was extracted into dichloromethane. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to give 2-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)azetidin-3-yl]methyl}benzamide (0.20 g, 64%) which was used without further purification. Propane-1-sulfonyl chloride (0.04 ml, 0.34 mmol) was added to 2-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)azetidin-3-yl]methyl}benzamide (0.10 g, 0.28 mmol) and triethylamine (0.08 g, 0.56 mmol) in dichloromethane (2 ml) at 0° C. The reaction was then stirred at room temperature for 30 mins before quenching with N,N-dimethylethylenediamine (0.5 eq). The resulting mixture was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. Purification by flash column chromatography on a silica cartridge eluting with dichloromethane (containing 1% ammonia) on a gradient of methanol (0-5%) led to 2-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)-1-(propylsulfonyl)azetidin-3-yl]methyl}benzamide as an off-white solid. m/z (M++H) 464, 1H NMR (500 MHz, DMSO): δ 9.34 (s, 1 H); 7.58 (t, J=6.7 Hz, 1 H); 7.43 (s, 1 H); 4.07 (t, J=12.7 Hz, 1H); 3.91 (d, J=7.8 Hz, 1 H); 3.79 (d, J=7.8 Hz, 2 H); 3.65 (d, J=8.1 Hz, 1 H); 3.53 (d, J=10.8 Hz, 1 H); 3.17 (s, 2 H); 3.05 (t, J=7.4 Hz, 2 H); 2.80 (s, 1 H); 2.56 (s, 2 H); 1.75 (s, 1 H); 1.67 (dd, J=7.8, 15.0 Hz, 5 H); 1.39 (s, 2 H); 0.96 (t, J=7.3 Hz, 3 H).
Reaction SMILES: OC[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.N1C=CC=CC=1OCCC1C=CC(OC(=O)N(C)C2C=CC=CC=2)=CC=1>>[O:21]=[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]1[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:9]=1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Reactant: Oc1ccccn1
Agent: CN(C(=O)Oc1ccc(CCOc2ccccn2)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(Cn2ccccc2=O)cc1)c1ccccc1
Yield: 29 %

Procedure:
The title compound was prepared in 29% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 2-hydroxypyridine. In addition 50% of the isomeric methyl-phenyl-carbamic acid 4-[2-(pyridin-2-yloxy)-ethyl]-phenyl ester was isolated, see characterization below. 1H NMR (400 MHz; CDCl3): δ 3.05 (t, 2H), 3.41 (br s, 3H), 4.14 (s, 2H), 6.08 (t, 1H), 6.66 (d, 1H), 6.90 (dd, 1H), 7.02 (br s, 2H), 7.10 (d, 2H), 7.25–7.42 (m, 6H); HPLC-MS: m/z=349.2 (M+1); Rt=3.04 min.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5](/[C:9](/[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[N:10]\[NH:11]C(OC(C)(C)C)=O)=[C:4](F)[CH:3]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:9]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[N:10][NH:11]2)=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N/N=C(/c1ccncc1)c1cc(F)c(Br)cc1F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Fc1cc2c(-c3ccncc3)n[nH]c2cc1Br
Yield: 84.7 %

Procedure:
A solution of 1,1-dimethylethyl (2Z)-2-[(4-bromo-2,5-difluorophenyl)(4-pyridinyl)methylidene]hydrazinecarboxylate (Intermediate 3, 250 mg) and DBU (95 μ) in THF (3 ml) was stirred at 150° C. in a microwave oven. After 30 min the mixture was partitioned between water and ethyl acetate and the organic layer was washed with water and brine, dried using a hydrophobic filter tube and concentrated under vacuum to give the title compound as an orange solid (150 mg).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][CH2:12][OH:13].[OH-].[Na+].C(O)(=[O:18])C>O>[OH:13][CH2:12][CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:2](=[O:18])[NH:10][CH:9]=[N:8][C:7]1=2
Reactant: CC(=O)O
Reactant: OCCn1cnc2c(Cl)ncnc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]cnc2c1ncn2CCO

Procedure:
6-Chloro-9-hydroxyethyl purine, III (4 g), was added slowly to warm N NaOH (30 ml) and refluxed for 2 hr. The reaction is cooled in ice and neutralized with glacial acetic acid. After filtration, portions of unreacted III are removed. The product is recrystallized from methanol and washed with acetone. Colorless crystals. Yield, 1 g. (28%) mp. 274°; uv (H2O, pH 5.5), λmax 250 nm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1.[C:28]1([CH2:36]O)[CH:33]=[CH:32][C:31]([CH2:34][OH:35])=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[OH:35][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:36][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Reactant: OCc1ccc(CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(CO)cc3)n2)c1C(F)(F)F
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of the title compound of Example 1 Step B (150 mg, 0.40 mmol) and 1,4-benzenedimethanol (165 mg, 1.19 mmol) in THF (2 mL) were added triphenylphosphine (313 mg, 1.19 mmol), followed by diisopropyl azodicarboxylate (0.232 mL, 1.19 mmol). The reaction vial was capped and stirred at 60° C. After 1.5 h, the reaction mixture was allowed to cool to ambient temperature, then was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 40% EtOAc in hexanes, then 40 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 498.1 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.95 (dd, J=8.0, 1.5 Hz, 1H), 7.85 (t, J=7.5 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.39-7.28 (m, 5H), 7.11 (t, J=7.5 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 5.15 (s, 2H), 4.98-4.94 (m, 2H), 4.38 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[CH2:19]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCBr
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCOc1ccc2c(=O)c(-c3ccccc3)coc2c1
Yield: 62.1 %

Procedure:
23.8 g of 7-hydroxy-isoflavone in 200 ml of anhydrous acetone are boiled, under stirring, with 18 g of n-hexyl bromide, 18 g of potassium carbonate and 1 g of potassium iodide for 72 hours under reflux condenser. The inorganic salts are removed by filtration, the filtrate is subjected to steam distillation in order to remove acetone and excess reagent, the precipitate is filtered and recrystallized from acetone, yielding 20 g of 7-n-hexyloxy-isoflavone, m.p. 120°-122° C. In a similar way, also 7-isopropyloxy-isoflavone, 7-n-butyloxy-isoflavone, and 7-n-amyloxy-isoflavone already characterized in Example 1, 7-isopropyloxy-2-methyl-isoflavone, 7-n-butyloxy-isoflavone and 7-n-amyloxy-isoflavone already characterized in Example 5, and
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[NH:11]1[C:15]2[N:16]=[CH:17][CH:18]=[C:19]([CH:20]=O)[C:14]=2[CH:13]=[CH:12]1.C([SiH](CC)CC)C.[OH-].[Na+].C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:11]1[C:15]2=[N:16][CH:17]=[CH:18][C:19]([CH2:20][NH:10][C:9]3[CH:8]=[CH:7][S:6][C:5]=3[C:3]([O:2][CH3:1])=[O:4])=[C:14]2[CH:13]=[CH:12]1
Reactant: COC(=O)c1sccc1N
Reactant: O=Cc1ccnc2[nH]ccc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1sccc1NCc1ccnc2[nH]ccc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
A solution of 3-aminothiophene-2-carboxylic acid methyl ester (110 mg, 0.701 mmol), and 1H-Pyrrolo[2,3-b]pyridine-4-carboxaldehyde (107 mg, 0.736 mmol) in TFA/CH2Cl2 (2 mL/2 mL) was stirred at 50° C. for 3 hr. The solution was cooled to 0° C. and triethylsilane (0.224 mL, 1.40 mmol) was added dropwise. The mixture was then stirred at 50° C. for 4 hr and treated with 2 N NaOH (aq)(to pH 6) and then saturated NaHCO3 (aq)(to pH 8). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over silica gel (gradient of 20% EtOAc/Hexanes to 70% EtOAc/Hexanes) to yield methyl 3-[(1H-Pyrrolo[2,3-b]pyridin-4-ylmethyl)amino]thiophene-2-carboxylate (98 mg, 49 %). MS (ES+): 287 [MH+]. 1H NMR (DMSO-d6,400 MHz): δ 3.75 (s, 3H), 4.84 (d, 2H, J=4.4 Hz), 6.74 (dd, 1H, J=2.8 Hz & 2.0 Hz), 6.70 (d, 1H, J=5.6 Hz), 7.01 (d, 1H, J=4.8 Hz), 7.51 (t, 1H, J=2.4 Hz), 7.61 (d, 1H, J=5.2 Hz), 8.18 (d, 1H, J=4.8 Hz).
Reaction SMILES: CC1(C)CO[C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12]([CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:11][CH2:10]3)=[N:3]1.P(Cl)(Cl)(Cl)=O.N.[BrH:36]>N1C=CC=CC=1.CC(C)=O.O>[CH3:27][N:26]([CH2:25][CH2:24][CH2:23][C:12]1([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[O:11][CH2:10][C:9]2[CH:8]=[C:7]([C:4]#[N:3])[CH:15]=[CH:14][C:13]1=2)[CH3:28].[BrH:36]
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C3=NC(C)(C)CO3)ccc21
Agent: Br
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CC(C)=O
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 115.5 °C

Procedure:
To a stirred solution of 4,4-dimethyl-2-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-yl]oxazoline (287 g, 0.724 mol) in pyridine (1000 ml), at 5° C., phosphorous oxychloride (135 ml, 1.474 mol) is slowly added while keeping the temperature at 5 to 10° C. The mixture is heated at reflux (115-116° C.) for 3 to 4 hours. The mixture is cooled to about 10° C. and treated with deionized water (3200 mL), and the pH is adjusted to about pH 9 by addition of 28% aqueous ammonia (800 ml). The product is extracted with of toluene (1500+1000+500+500 ml) and the combined organic phases are decoloured with charcoal. The organic phase is concentrated under reduced pressure at 60-70° C. to give an oily residue to which acetone (3000 ml) is added. The acetone solution is cooled to 10° C. and treated with 60 ml 48% HBr to a pH value of 4-5. The solvent is evaporated under reduced pressure and the residue is taken up in acetone (800 ml). The mixture is heated to 40-50° C. and thereafter cooled to 5° C. After 15 hours at 5° C. the product is filtered off, washed with cold acetone (500 ml) and dried in vacuo at 50° C. 175-180 g of citalopram hydrobromide with a purity (HPLC, peak area)≧90% is obtained.
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+].[ClH:40]>CO>[ClH:40].[NH2:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH2:6][OH:7])[CH2:11][OH:12]
Reactant: CCCCCCCCCCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCCCCC(N)(CO)CO

Procedure:
2-Acetamido-1,3-diacetoxy-2-docosylpropane (1.5 g) was dissolved in 40 ml of methanol and 9.6 ml of a 1 N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 6 hours., The mixture was neutralized with a 1 N aqueous hydrochloric acid solution and concentrated under reduced pressure. The concentrate was washed with water and ethyl acetate:hexane=1:1 in order to give 846 mg of 2-amino-2-docosyl-1,3-propanediol hydrochloride.
Reaction SMILES: [N:1]([C@@H:4]([CH3:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:18][CH2:17][CH:16]([O:19]C(OCC)C)[CH2:15][C:13]3=2)[CH:8]=[N:7]1)=[N+:2]=[N-:3].C(OC1C=C2C(C=NN2C[C@@H](O)C)=CC=1)C1C=CC=CC=1>>[N:1]([C@@H:4]([CH3:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:18][CH2:17][CH:16]([OH:19])[CH2:15][C:13]3=2)[CH:8]=[N:7]1)=[N+:2]=[N-:3]
Reactant: CCOC(C)OC1COc2ccc3cnn(C[C@H](C)N=[N+]=[N-])c3c2C1
Agent: C[C@H](O)Cn1ncc2ccc(OCc3ccccc3)cc21
Product: C[C@@H](Cn1ncc2ccc3c(c21)CC(O)CO3)N=[N+]=[N-]

Procedure:
This compound was synthesized by following the procedure described in Example 2, Step I but using 1-((S)-2-azidopropyl)-8-(1-ethoxyethoxy)-1,7,8,9-tetrahydropyrano[2,3-g]indazole, which was prepared from (S)-1-(6-benzyloxyindazol-1-yl)-propan-2-ol instead of (R)-1-(6-benzyloxyindazol-1-yl)-propan-2-ol as described: oil (0.45 g, 79%); LC/MS (+APCI) m/z 274 (M+H).
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].N1C=CN=C1.[CH:11]1([C@@:17]([OH:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](=[O:20])[CH3:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCOCC>CN(C=O)C>[CH:21]1([C@:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([O:27][Si:2]([CH3:4])([CH3:3])[CH3:1])[C:18](=[O:20])[CH3:19])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(=O)[C@](O)(c1ccccc1)C1CCCCC1
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)[C@](O[Si](C)(C)C)(c1ccccc1)C1CCCCC1
Temperature: 85 °C
Yield: 68.7 %

Procedure:
To a solution of 12 ml (95 mmoles) of trimethylsilyl chloride and 11.6 g (172 mmoles) of imidazole in 100 ml of DMF was added 20 g (86 mmoles) of (R)-1-cyclohexyl-1-hydroxy-1-phenyl-2-propanone. This mixture was heated to 85° C. overnight. The next day, the mixture was cooled and poured onto a mixture of 100 ml of petroleum ether and 100 ml of ether. This was extracted with water. The organic layer was separated, dried, and the solvent removed. The residue was chromatographed on silica gel with hexane as the eluent to give 18.0 g of clear oil. IR 2950, 1730 cm-1NMR (CDCl3) δ7.4(m, 5H), 2.3(t, 1H), 2.1(s, 3H), 1.9-1.0(m, 10H), 0.3(s, 9H).
Reaction SMILES: [CH3:1][O:2][Si:3]([O:10][CH3:11])([O:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7].[CH:12]([N:15]=[C:16]=[N:17][CH:18]([CH3:20])[CH3:19])([CH3:14])[CH3:13]>>[CH:18]([NH:17][C:16]([NH:7][CH2:6][CH2:5][CH2:4][Si:3]([O:8][CH3:9])([O:10][CH3:11])[O:2][CH3:1])=[N:15][CH:12]([CH3:14])[CH3:13])([CH3:20])[CH3:19]
Reactant: CC(C)N=C=NC(C)C
Reactant: CO[Si](CCCN)(OC)OC
Product: CO[Si](CCCNC(=NC(C)C)NC(C)C)(OC)OC

Procedure:
A mixture of 11.74 g of (3-(trimethoxysilyl)propyl)amine (0.0654 mol) and of 9.9 g of diisopropylcarbodiimide (0.0785 mol, 20% excess) was heated for 6 h 30 min at 80° C. Analysis by GC then showed an amine conversion of greater than 97%. The final colorless mixture was evaporated to dryness at 100° C. under 2 mbar for 2 h to give 22.5 g of a colorless, low-viscosity liquid corresponding to the expected guanidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[C:7]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:5])[CH3:2].[F:34][C:35]([F:46])([F:45])[C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:39]3[CH:40]=[CH:41][C:36]([C:35]([F:46])([F:45])[F:34])=[CH:37][CH:38]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[C:7]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(N2CCOCC2)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(N2CCOCC2)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-morpholin-4-yl-phenyl)indole-3-carboxylic acid ethyl ester (158 mg, 0.35 mmol, see step (b) Example 15) and 4-trifluoromethylphenylboronic acid (100 mg, 0.53 mmol). Yield 120 mg (57%).