Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:23]3[CH:32]=[C:31]([CH3:33])[C:26]([C:27]([O:29]C)=[O:28])=[CH:25][N:24]=3)[C:13]=2[O:14]COCC[Si](C)(C)C)=[CH:5][CH:4]=1)#[N:2].CO.[Li+].[OH-]>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:23]3[CH:32]=[C:31]([CH3:33])[C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cnc(-n2ncc(-c3ccc(C#N)cc3)c2OCOCC[Si](C)(C)C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(-n2ncc(-c3ccc(C#N)cc3)c2O)ncc1C(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
Combined methyl 6-(4-(4-cyanophenyl)-5-((2-(trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-1-yl)-4-methylnicotinate (8.67 g, 25.96 mmol), methanol (50 mL), water (50 mL) and LiOH (3.27 g, 77.87 mmol). The reaction mixture was stirred at room temperature for 6 h and at 50° C. overnight. The reaction mixture was concentrated to remove most of the methanol and then the pH was adjusted to 3 by addition of 3N HCl to give a solid. The solid was collected by filtration and dried in vacuum to give the title compound (4.3 g, 51.76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[N:9]2[NH:15]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOC(C)=O>[NH2:15][N:9]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12][CH2:11][C:10]1=[O:14]
Reactant: CC(C)(C)OC(=O)NN1C(=O)CCCC1c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: NN1C(=O)CCCC1c1ccc(F)cc1
Reaction time: 2 h
Yield: 89.8 %

Procedure:
Step AAG (3): To a soln of tert-butyl 2-(4-fluorophenyl)-6-oxopiperidin-1-ylcarbamate (330 mg, 1.07 mmol) in CH2Cl2 (5 mL) was added TFA (1.00 mL, 13.0 mmol). The mixture was stirred at for 2 hrs. The solvent was removed in vacuo. The crude reaction was diluted with EtOAc (100 mL). The organic layer was separated and washed with saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered, and concentrated in vacuo to afford 1-amino-6-(4-fluorophenyl)piperidin-2-one (200 mg, 90% yield). LC-MS (M+H)+ 209.26.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:21][CH2:20][C:15]4(OCC[O:16]4)[CH2:14][CH2:13]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.N>O>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:13][CH2:14][C:15](=[O:16])[CH2:20][CH2:21]3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2noc(N3CCC4(CC3)OCCO4)n2)cc1
Agent: Cl
Agent: N
Solvent: O
Product: O=C1CCN(c2nc(-c3ccccc3)no2)CC1

Procedure:
A mixture of 8-(3-phenyl-[1,2,4]oxadiazol-5-yl)-1,4-dioxa-8-aza-spiro[4.5]decane (660 mg), conc. aqueous HCl (5 mL), and water (5 mL) is kept at room temperature over night. The mixture is basified with conc. aqueous ammonia and the precipitate is filtered off and dissolved in dichloromethane. The resulting solution is dried over Na2SO4 and concentrated in vacuo to give the title compound. TLC: rf=0.33 (silica gel, hexane/ethyl acetate 2:1); Mass spectrum (ESI+): m/z=244 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:21])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:3].C(N(CC)C(C)C)(C)C.Br[C:32]1[N:40]=[CH:39][N:38]=[C:37]2[C:33]=1[NH:34][CH:35]=[N:36]2>C(O)(C)(C)C>[N:40]1[C:32]([NH:1][C@@H:2]([C:4]2[O:5][C:6]3[C:11]([C:12](=[O:21])[C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH3:3])=[C:33]2[C:37]([NH:36][CH:35]=[N:34]2)=[N:38][CH:39]=1
Reactant: C[C@@H](N)c1oc2ccccc2c(=O)c1-c1cccc(F)c1
Reactant: Brc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C[C@@H](Nc1ncnc2[nH]cnc12)c1oc2ccccc2c(=O)c1-c1cccc(F)c1

Procedure:
This example is also described in Example 56 of WO 2011/055215. To a solution of (R)-2-(1-Amino-ethyl)-3-(3-fluoro-phenyl)-chromen-4-one (0.41 g, 1.52 mmoles) in tert-butanol (7 ml), N,N-diisopropylethylamine (0.53 ml, 3.04 mmoles) and 6-bromopurine (0.242 g, 1.21 mmoles) are added and refluxed for 24 h. The reaction mixture is concentrated, diluted with water, and extracted with ethyl acetate. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product is purified by column chromatography with methanol:ethyl acetate to afford the title compound as an off-white solid. MP: 274-276° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 12.96 (s, 1H), 8.14-8.01 (m, 4H), 8.11 (s, 1H), 7.81 (dt, J=8.5, 1.5 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.49 (m, 2H), 7.25-7.19 (m, 3H), 5.18 (br m, 1H), 1.56 (d, J=7.0 Hz, 3H). Mass: 402.04 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10](I)[C:3]=12.[OH:30][CH2:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:31][OH:30])[CH:37]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(I)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Reactant: OCc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1ncnc2c1c(-c1cccc(CO)c1)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 48.8 %

Procedure:
To a solution of Example 57a (0.250 g, 0.50 mmoles) in DMF (5 ml), ethanol (2.5 ml) and water (2.5 ml), 3-hydroxymethylphenylboronic acid (0.115 g, 0.757 mmoles) and sodium carbonate (0.267 g, 2.53 mmoles) were added and the system is degassed for 30 min. Tetrakis triphenylphosphine Palladium (0.115 g, 0.099 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.116 g, 44% yield). MP: 219-223° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.23 (s, 1H), 8.05 (dd, J=8.0, 1.6 Hz, 1H), 7.77 (m, 1H), 7.58 (s, 1H), 7.50 (m, 3H), 7.44 (d, J=8.5 Hz, 1H), 7.41-7.31 (m, 6H), 5.52 (s, 2H), 5.27 (t, J=5.8 Hz, 1H), 4.57 (d, J=5.7 Hz, 2H). Mass: 476.31 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1>CCOC(C)=O.[Pd]>[NH2:18][C:16]1[CH:15]=[CH:14][C:4]([O:5][CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]2)=[C:3]([O:2][CH3:1])[CH:17]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(O)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1OCCN1CCC(O)C1
Yield: 80.6 %

Procedure:
1-[2-(2-methoxy-4-nitrophenoxy)ethyl]pyrrolidin-3-ol (0.169 g, 0.583 mmol) was taken up in EtOAc (5 mL) and 10% Pd/C (0.016 g) was added. The hydrogen gas was bubbled through the reaction and the reaction then placed under a hydrogen blanket. Stirred over night. Filtered through celite and concentrated to give 0.118 g (0.470 mmol, 81%) of the desired product. 1H NMR (CDCl3) δ 6.74 (d, 1H, J=8.5 Hz), 6.28 (s, 1H), 6.19 (d, 1H, J=8.5 hz), 4.34 (m, 1H), 4.05 (t, 2H, J=6.2 Hz), 3.79 (s, 3H), 3.03-2.83 (m, 5H), 2.63-2.59 (m, 1H), 2.42-2.38 (m, 1H), 2.23-2.14 (m, 1H), 1.75 (m, 1H).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:24][S:25](O)(=[O:27])=[O:26].P(Cl)(Cl)(Cl)=O>ClCCl>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH2:19][C:20]([CH3:22])([CH3:21])[CH3:23])([CH3:18])[CH3:17])=[CH:12][C:11]=1[S:25]([Cl:24])(=[O:27])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C(C)(C)CC(C)(C)C)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCOc1ccc(C(C)(C)CC(C)(C)C)cc1S(=O)(=O)Cl

Procedure:
In 900 ml of dichloromethane was dissolved 159 g of Compound A and the solution was stirred while cooling with an ice bath. After slowly adding dropwise 41.5 ml of chlorosulfonic acid to the solution, the mixture was stirred for 1.5 hours. Then, dichloromethane was removed while reducing the pressure by a tap aspirator and 480 ml of N,N-dimethylacetamide and 150 ml of acetonitrile were added to the residue formed. After adding dropwise 93.2 ml of phosphorous oxychloride to the mixture over a period of 40 minutes, the resultant mixture was stirred for 1.5 hours at 40° C. The solution was extracted four times with 500 ml of hexane and the hexane layer was collected and concentrated to provide 229 g of a crude product of 2-octyloxy-5-t-octylbenzenesulfonyl chloride (Compound B). The crude product was used as it was in the subsequent reaction.
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:14]C1C=CC(C(=O)C)=CC=1.C(OC)(=O)CC>>[F:14][C:4]1[CH:5]=[CH:6][C:1]([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10][CH3:11])=[CH:2][CH:3]=1
Reactant: CCC(=O)CC(=O)c1ccccc1
Reactant: CC(=O)c1ccc(F)cc1
Solvent: CCC(=O)OC
Product: CCC(=O)CC(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared (as described above for Intermediate 16) from 0.525 g of 4′-fluoroacetophenone and 0.73 mL of methyl propionate to yield 120 mg of Intermediate 32: TLC analysis: Rf=0.77 (2/1, hexanes/EtOAc); 1H NMR (400 MHz, CDCl3, enol form) δ7.98 (d, 2H, J=8.3), 7.7 (d, 2H, J=8.3), 6.12 (s, 1H), 1.55 (s, 3H); low resolution mass spectrum (ES+) 195 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[CH2:38][C:39](O)=[O:40]>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[CH2:38][C:39]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:40]
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Reactant: O=C(O)Cc1cc(F)ccc1F
Product: O=C(Cc1cc(F)ccc1F)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1

Procedure:
The title compound was synthesized from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-phenyl-2-pyrimidine (see Example 3, Step H) and (2,5-difluorophenyl)acetic acid using the coupling conditions described in Example 5. 1H NMR (400 MHz, DMSO-d6): δ 3.76 (s, 2H), 6.53 (d, 1H, J=5.3 Hz), 6.94 (m, 1H), 7.10-7.27 (m, 7H), 7.41-7.48 (m, 2H), 7.69-7.76 (m, 3H), 7.89 (m, 1H), 8.27 (d, 1H, J=5.3 Hz), 8.48 (m, 1H), 8.83 (m, 1H), 9.56 (s, 1H), 10.39 (s, 1H). ES-LC/MS m/z=533 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]([CH2:10]O)=[CH:8][CH:7]=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:5]=1.O=S(Cl)[Cl:24]>C(Cl)Cl>[Cl:24][CH2:10][C:9]1[C:4]([CH2:3][O:2][CH3:1])=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Solvent: ClCCl
Product: COCc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl

Procedure:
0.311 g (1.046 mmol) of the above prepared [2-methoxymethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol was dissolved in 4 ml of CH2Cl2 and treated at 0C. with 0.15 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° C. for 5 Min. and at ambient temperature for 60 Min. Pouring onto crashed ice/NaHCO3, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents produced 0.330 g of pure title compound as colorless oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[P:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[SiH](Cl)Cl>C1(C)C(C)=CC=CC=1>[CH3:1][S:2]([NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[P:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: Cl[SiH](Cl)Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 150 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
3.93 gram (7.17 mmol) of (−)-2-methylsulfonylamino-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (1-3a-1)) was dissolved in 179 ml of xylene in an autoclave, followed by the addition of 20.0 ml (143.4 mmol) of triethylamine at 0° C. over 15 minutes and 3.62 ml (35.8 mmol) of trichlorosilane over 30 minutes. The mixture was stirred at 150° C. for 18 hours in a tightly sealed condition. The reaction mixture was then extracted with 300 ml of ether. The extract was washed with 100 ml of saturated aqueous solution of ammonium chloride and 100 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 1:6 mixture of ethyl acetate and hexane) to obtain 3.35 gram of the titled compound.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]3[N:22]4[CH2:23][CH2:24][O:25][CH2:26][C:21]4=[N:20][C:14]=3[C:15]([NH2:19])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.Br>C(O)(=O)C>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]3[CH2:26][O:25][CH2:24][CH2:23][N:22]3[C:13]=2[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[N:16]=1
Reactant: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc1n2CCOC1
Agent: Br
Solvent: CC(=O)O
Product: Nc1nc2cc(O)ccc2c2c1nc1n2CCOC1
Temperature: 100 °C

Procedure:
A glass vial was charged with 3-(benzyloxy)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (0.1 g, 0.29 mmol) and a solution of 48% hydrogen bromide in acetic acid (4.0 mL). The mixture was heated at 100° C. overnight, cooled, and concentrated to provide 6-amino-10,11-dihydro-8H-[1,4]oxazino [4′,3′:1,2]imidazo[4,5-c]quinolin-3-ol as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.F[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[C:4](=[O:20])[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[N:6][N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:8]=1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Reactant: Fc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1cn(-c2ccccn2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 72 h
Yield: 25.9 %

Procedure:
A suspension of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (60 mg), 2-fluoropyridine (65 mg) and cesium carbonate (364 mg) in NMP (2 mL) was stirred at 100° C. for 3 days, 1M hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol) to give the title compound (20 mg).
Reaction SMILES: [P:1]([O-:50])([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][N+:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([O:3][CH2:4][CH:5]([O:26]C(=O)C1C=CC=CC=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>CO>[P:1]([O-:50])([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][N+:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)([O:3][CH2:4][CH:5]([OH:26])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCCCCCCC[n+]1ccccc1)OC(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOCC(O)COP(=O)([O-])OCCCCCCCC[n+]1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
1.76 g (2.45 mmole) of 2-benzoyloxy derivative synthesized in Example 30 was dissolved in 5 ml of methanol and an aqueous solution containing 11.2 g (4.90 mmole) of 10% tetrabutylammonium hydroxide was added thereto. The mixture was stirred at room temperature for 2 hours and then subjected to the coupled two columns, one containing 40 ml of Amberlite IR-410 and the other 20 ml of Amberlite IR-120 and eluted with 95% hydrous tetrahydrofuran. The eluate was concentrated to dryness and the residue was subjected to column chromatography on 25 g of silica gel. A mixture of chloroform-methanol-water (65:25:4) was used for elution. The desired fraction was concentrated under reduced pressure to give 1.13 g (yield: 75%) of 2-(hydroxy)-3-(octadecyloxy)propyl 8-pyridiniooctyl phosphate as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[OH:20])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=Cc1cccnc1
Reactant: COc1ccc([Mg]Br)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cccnc2)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(3,4-Dimethoxyphenyl)magnesium bromide (0.5 M in THF, 9.5 mL, 4.75 mmol) was added dropwise by syringe to a solution of nicotinaldehyde (0.88 mL, 9.37 mmol) in dry THF (20 mL) at 0° C. The reaction mixture was stirred for 30 minutes at 0° C., then quenched with saturated aqueous ammonium chloride solution. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-60% EtOAc-hexanes) to provide the title compound as a brown oil.
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19](O)=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][OH:26]>>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]([NH:23][CH2:24][CH2:25][OH:26])=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: NCCO
Product: O=C(Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12)NCCO

Procedure:
The title compound was prepared according to the procedure described in Example 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2) and 2-aminoethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]>[Ni].N>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1ccc(C(F)(F)F)cc1Cl
Agent: [Ni]
Agent: N
Product: NCc1ccc(C(F)(F)F)cc1Cl
Reaction time: 20 h

Procedure:
A suspension of 1.000 g (4.865 mmol) 2-chloro-4-trifluoromethyl-benzonitrile and 100 mg Raney nickel in conc. methanolic ammonia was hydrogenated for 20 h at RT and 3 bar. The catalyst was filtered off and the filtrate was evaporated down i. vac.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:15])(=O)=O)=CC=1.[Br:23][C:24]1[CH:25]=[C:26]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35](O)[N:34]=2)[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:23][C:24]1[CH:25]=[C:26]([NH:32][C:33]2[N:34]=[C:35]([O:11][CH2:12][CH2:13][N:14]([CH3:15])[C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH:36]=[CH:37][CH:38]=2)[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)C(=O)OC(C)(C)C)cc1
Reactant: Cn1cc(Br)cc(Nc2cccc(O)n2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(CCOc1cccc(Nc2cc(Br)cn(C)c2=O)n1)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 4 h
Yield: 22.1 %

Procedure:
A mixture of 112b (3.3 g, 10 mmol), 5-Bromo-3-(6-hydroxypyridin-2-ylamino)-1-methylpyridin-2(1H)-one 101a (7.4 g, 25 mmol) and Cs2CO3 (4.1 g, 12.5 mmol) in DMF (40 mL) was stirred at 100° C. for 4 h. The mixture partitioned between EA and water. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give tert-butyl 2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yloxy)ethyl(methyl)carbamate 112c (1.0 g, 22%) as a yellow solid. ESI-LCMS: m/z=454.9
Reaction SMILES: O1CCOC1.[O:6]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:26][N:27]3[CH:31]=[N:30][CH:29]=[N:28]3)[O:23][CH:22]([CH2:24][OH:25])[CH2:21][O:20]2)=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1>O1CCOCC1>[O:6]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:26][N:27]3[CH:31]=[N:30][CH:29]=[N:28]3)[O:23][CH:22]([CH2:24][O:25][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([Cl:34])=[CH:36][CH:37]=3)[CH2:21][O:20]2)=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: OCC1COC(Cn2cncn2)(c2ccc(Oc3ccccc3)cc2)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCO1
Solvent: C1COCCO1
Product: Clc1ccc(COCC2COC(Cn3cncn3)(c3ccc(Oc4ccccc4)cc3)O2)cc1
Temperature: 25 °C

Procedure:
14,1 parts of 2-[p-(Phenoxy)-phenyl]-2-(1H-1,2,4-triazolyl-methyl)-4-hydroxymethyl-1,3-dioxolane dioxolane dissolved in 100 ml absolute dioxane and then 1,8 parts of 55 % sodium hydrid dispersion in 100 ml absolute dioxane are stirred in at room temperature while introducing nitrogen. The mixture is heated 3 hours to 80° C., then cooled to room temperaLure, treated dropwise within 30 minutes with 8,6 parts of p-chlorobenzylbromide dissolved in 50 parts of absolute dioxane. The reaction mixture is beated 3 hours to 50° C., then cooled to room temperature, diluted with 1200 ml ice-water and extracted with three 200 ml portions of ethyl acetate. The combined extracts are washed with two 70 ml portions of water, dried over sodium sulfate, filtered and the solvent removed by evaporation. The remaining diastereoisomers are separated by column chromatography (silica gel/ethyl acetate). The eluant is then removed by evaporation to give the diastereoisomer B in the form of crystals with a melting point of 83°-85° C. The diastereoisomer A is obtained after the evaporation of the solvent in form of a viscous slightly brownish oil; nD26 : 1.5865.